Tricyclic pyridyl carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists

ABSTRACT

This invention provides novel substituted tricyclic pyridyl carboxamides which act as oxytocin receptor competitive antagonists, as well as methods of their manufacture, pharmaceutical compositions and methods of their use in treatment, inhibition, suppression or prevention of preterm labor, dysmenorrhea, endometritis, suppression of labor at term prior to caesarean delivery, and to facilitate antinatal transport to a medical facility. These compounds are also useful in enhancing fertility rates, enhancing survival rates and synchronizing estrus in farm animals; and may be useful in the prevention and treatment of disfunctions of the oxytocin system in the central nervous system including obsessive compulsive disorder (OCD) and neuropsychiatric disorders.

This application claims priority from provisional application Ser. No.60/283,262, filed Apr. 12, 2001, the entire disclosure of which ishereby incorportated by reference.

This invention concerns novel tricyclic pyridyl carboxamides which actas oxytocin receptor antagonists, as well as methods of theirmanufacture, methods of treatment and pharmaceutical compositionsutilizing these compounds. The compounds of the present invention areuseful therapeutic agents in mammals, particularly in humans. Morespecifically, they can be used in the prevention and/or suppression ofpreterm labor, for the suppression of labor at term prior to caesareandelivery, to facilitate antinatal transport to a medical facility, andfor the treatment of dysmenorrhea. These compounds also useful inenhancing fertility rates, enhancing survival rates and synchronizingestrus in farm animals; and may be useful in the prevention andtreatment of disfunctions of the oxytocin system in the central nervoussystem including obsessive compulsive disorder (OCD) andneuropsychiatric disorders.

BACKGROUND OF THE INVENTION

Premature labor remains the leading cause of perinatal mortality andmorbidity. Infant mortality dramatically decreases with increasedgestational age. The survival rate of prematurely born infants increasesfrom 20% at 24 weeks to 94% at 30 weeks. Moreover the cost associatedwith the care of an infant born prematurely is very high. While manyagents have been developed for the treatment of premature labor in thelast 40 years, the incidence of pre-term births and low birth weightinfants has remained relatively unchanged. Therefore there remains anunmet need for the development of a safe and effective treatment ofpreterm labor.

Tocolytic (uterine relaxing) agents currently in use include β₂adrenergic receptor agonists such as Ritodrine which is moderatelyeffective in suppressing preterm labor, but it is associated withmaternal hypotension, tachycardia, and metabolic side effects. Severalother agents have been used to suppress premature labor, including otherβ₂ adrenergic agonists (terbutaline, albuterol), magnesium sulfate,NSAIDs (indomethacin), and calcium channel blockers. The consensus isthat none of these agents is very effective; there is no clinicalevidence showing that these compounds can prolong gestation for morethan 7 days (Johnson, Drugs, 45, 684–692 (1993)). Furthermore, theirsafety profile is not ideal. Adverse effects include respiratorydepression and cardiac arrest (magnesium sulfate), hemodynamic effects(calcium channel blockers), premature closure of the ductus arteriosusand oligohydramnios (NSAIDS; prostaglandin synthase inhibitors).Therefore there is an unmet need for safer and more efficacious agentsfor the treatment of preterm labor with better patient tolerability.Specific requirements with regard to safety include a product with no orlow rates of tachycardia, limited anxiety, improved fetal safety, andfew, if any, adverse cardiovascular effects.

One target of interest is the oxytocin receptor in the uterus, and aselective oxytocin receptor antagonist has been proposed as an idealtocolytic agent. While the exact role of oxytocin (OT) in parturitionhas not been clearly defined, there is evidence strongly suggesting thatit may play a critical role in the initiation and progression of laborin humans (Fuchs et al. Science 215, 1396–1398 (1982); Maggi et al. J.Clin. Endocrinol. Metab. 70, 1142–1154 (1990); Åkerlund, Reg. Pept 45,187–191 (1993); Åkerlund, Int. Congr. Symp. Semin. Ser., Progress inEndocrinology 3, 657–660 (1993); Åkerlund et al., in Oxytocin, Ed. R.Ivell and J. Russel, Plenum Press, New York, pp 595–600 (1995)).Preliminary clinical trials with oxytocin receptor antagonists supportthe concept that a blockade of OT receptors reduces uterine myometrialactivity and delays the onset of labor (Åkerlund et al., Br. J. Obst.Gynaecol. 94, 1040–1044, (1987); Andersen et al., Am. J. Perinatol. 6,196–199 (1989); Melin, Reg. Pept. 45, 285–288 (1993)). Thus, a selectiveoxytocin antagonist is expected to block the major effects of oxytocinexerted mainly on the uterus at term, and to be more efficacious thancurrent therapies for the treatment of preterm labor. By virtue of itsdirect action on the receptors in the uterus an oxytocin antagonist isalso expected to have fewer side effects and an improved safety profile.

The following references describe peptidic oxytocin antagonists: Hrubyet al., Structure-Activity Relationships of Neurohypophyseal Peptides,in The Peptides: Analysis, Synthesis and Biology; Udenfriend andMeienhofer Eds., Academic Press, New York, Vol. 8, 77–207 (1987);Pettibone et al., Endocrinology, 125, 217 (1989); Manning et al.,Synthesis and Some Uses of Receptor-Specific Agonists and Antagonists ofVasopressin and Oxytocin, J. Recept. Res., 13, 195–214 (1993); Goodwinet al., Dose Ranging Study of the Oxytocin Antagonist Atosiban in theTreatment of Preterm Labor, Obstet. Gynecol., 88, 331–336 (1996).Peptidic oxytocin antagonists suffer from a lack of oral activity andmany of these peptides are non-selective antagonists since they alsoexhibit vasopressin antagonist activity. Bock et al. [J. Med. Chem. 33,2321 (1990)], Pettibone et al. [J. Pharm. Exp. Ther. 256, 304 (1991)],and Williams et al. [J. Med. Chem., 35, 3905 (1992)] have reported onpotent hexapeptide oxytocin antagonists which also exhibit weakvasopressin antagonistic activity in binding to V₁ and V₂ receptors.

Various non-peptidic oxytocin antagonists and/or oxytocin/vasopressin(AVP) antagonists have recently been reported by Pettibone et al.,Endocrinology, 125, 217 (1989); Yamamura et al., Science, 252, 572–574(1991); Evans et al., J. Med. Chem., 35, 3919–3927 (1992); Pettibone etal., J. Pharmacol. Exp. Ther, 264, 308–314 (1992); Ohnishi et al., J.Clin. Pharmacol. 33, 230–238, (1993); Evans et al., J. Med. Chem. 36,3993–4006 (1993); Pettibone et al., Drug Dev. Res. 30, 129–142 (1993);Freidinger et al., General Strategies in Peptidomimetic Design:Applications to Oxytocin Antagonists, in Perspect. Med. Chem. 179–193(1993), Ed. B. Testa, Verlag, Basel, Switzerland; Serradeil-LeGal, J.Clin. Invest., 92, 224–231 (1993); Williams et al., J. Med. Chem. 37,565–571 (1994); Williams et al., Bioorg. Med. Chem. 2, 971–985 (1994);Yamamura et al., Br. J. Pharmacol., 105, 546–551 (1995); Pettibone etal., Advances in Experimental Medicine and Biology 395, 601–612 (1995);Williams et al., J. Med. Chem. 38, 4634–4636 (1995); Hobbs et al.,Biorg. Med. Chem. Lett. 5, 119 (1995); Williams et al., Curr. Pharm.Des. 2, 41–58 (1996); Freidinger et al., Medicinal Research Reviews, 17,1–16 (1997); Pettibone et al., Biochem. Soc. Trans. 25 (3), 1051–1057(1997); Bell et al., J. Med. Chem. 41, 2146–2163 (1998); Kuo et al.,Bioorg. Med. Chem. Lett. 8, 3081–3086 (1998); Williams et al., Biorg.Med. Chem. Lett. 9, 1311–1316 (1999).

Certain carbostyril derivatives and bicyclic azepines are disclosed asoxytocin and vasopressin antagonists by Ogawa et al. in WO 94/01113(1994); benzoxazinones are disclosed as oxytocin and vasopressinreceptor antagonists by Sparks et al. in WO 97/25992 (1997); Williams etal. disclose piperidine oxytocin and vasopressin receptor antagonists inWO 96/22775 (1996); Bock et al. disclose benzoxazinone andbenzopyrimidinone piperidines useful as oxytocin and vasopressinreceptor antagonists in U.S. Pat. No. 5,665,719 (1997); piperazines andspiropiperidines useful as oxytocin and vasopressin receptor antagonistsare disclosed by Evans et al. in U.S. Pat. No. 5,670,509 (1997) and byBock et al. in U.S. Pat. No. 5,756,504 (1998); Bell et al. disclosepiperazine oxytocin receptor antagonists in UK Patent Application, GB 2326 639 A (1998); Bell et al. disclose benzoxazinone and quinolinoneoxytocin and vasopressin receptor antagonists in UK Patent ApplicationGB 2 326 410 A (1998); Bell et al. disclose benzoxazinone oxytocin andvasopressin receptor antagonists in U.S. Pat. No. 5,756,497 (1998);Matsuhisa et al. disclose difluoro tetrahydrobenzazepine derivatives asoxytocin antagonists in WO 98/39325 (1998); Ogawa et al. discloseheterocyclic bisamides with vasopressin and oxytocin antagonist activityin U.S. Pat. No. 5,753,644 (1998); and Ogawa et al. disclose benzazepinederivatives with anti-vasopressin activity, oxytocin antagonisticactivity and vasopressin agonist activity, useful as vasopressinantagonists, vasopressin agonists and oxytocin antagonists in WO97/22591 (1997) and U.S. Pat. No. 6,096,736 (2000).

Trybulski et al. disclose 3-carboxamide derivatives ofpyrrolobenzodiazepine bisamides with vasopressin antagonist activity inU.S. Pat. No. 5,880,122 (1999); bicyclic thienoazepines with vasopressinand oxytocin receptor antagonist activity are disclosed by Albright etal. in WO 96/22294 (1996) and U.S. Pat. No. 5,654,297 (1997); andtricyclic benzazepines with vasopressin and oxytocin receptor antagonistactivity are disclosed by Albright et al. in WO 96/22282 (1996) and U.S.Pat. No. 5,849,735 (1998).

Albright et al. broadly disclose tricyclic benzazepine compounds whichpossess antagonistic activity at the V₁ and/or V₂ receptors and exhibitin vivo vasopressin antagonistic activity, as well as antagonisticactivity at the oxytocin receptors.

Venkatesan et al. broadly disclose tricyclic benzazepines withvasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,521,173(1996), WO 96/22292 (1996), and in U.S. Pat. No. 5,780,471 (1998).

Oxytocin antagonists can be useful for the treatment and/or preventionand/or suppression of preterm labor, for the suppression of term laborprior to a caesarian delivery, and to facilitate antinatal transport toa medical facility. They also can produce contraception in mammals giventhat oxytocin antagonists have been shown to inhibit the release ofoxytocin-stimulated luteneizing hormone (LH) from pituitary cells(Rettori et al., Proc. Nat. Acad. Sci. U.S.A. 94, 2741–2744 (1997);Evans et al., J. Endocrinol., 122, 107–116 (1989); Robinson et al., J.Endocrinol. 125, 425–432 (1990)).

Oxytocin antagonists also have the ability to relax uterine contractionsinduced by oxytocin in mammals and thus can be also useful for thetreatment of dysmenorrhea, a condition characterized by pain duringmenstruation (Åkerlund, Int. Congr. Symp. Semin. Ser., Progress inEndocrinology 3, 657–660 (1993); Åkerlund, Reg. Pept. 45, 187–191(1993); Melin, Reg. Pept. 45, 285–288 (1993)). Primary dysmenorrhea isassociated with ovulatory cycles, and it is the most common complaint ofgynecologic patients. Myometrial hypercontractility and decreased bloodflow to the uterus are thought to be causative factors for the symptomsof primary dysmenorrhea (Åkerlund, Acta Obstet. Gynecol. Scand. 66,459–461 (1987). In particular, vasoconstriction of small uterinearteries by vasopressin and oxytocin is thought to produce tissueischemia and pain (Jovanovic et al., Br. J. Pharmacol. 12, 1468–1474(91997); Chen et al., Eur. J. Pharmacol. 376, 25–51 (1999)).

The administration of oxytocin receptor antagonists to farm animalsafter fertilization has been found to enhance fertility rates byblocking oxytocin induced luteolysis leading to embryonic loss (Hickeyet al., WO 96/09824 A1 (1996), Sparks et al., WO 97/25992 A1 (1997);Sparks et al., U.S. Pat. No. 5,726,172 A (1998)). Thus, oxytocinreceptor antagonists can be useful in farm animal husbandry to controltiming of parturition and delivery of newborns resulting in enhancedsurvival rates. They can also be useful for the synchronization ofestrus by preventing oxytocin induced corpus luteum re.g.ression and bydelaying estrus (Okano, J. Reprod. Dev. 42 (Suppl.), 67–70 (1996)).Furthermore oxytocin receptor antagonists have been found to have apowerful effect in inhibiting oxytocin-induced milk ejection in dairycows (Wellnitz et al., Journal of Dairy Research 66, 1–8 (1999)).

Oxytocin is also synthesized in the brain and released in the centralnervous system. Recent studies have established the importance ofcentral oxytocin in cognitive, affiliative, sexual and reproductivebehavior, and in regulating feeding, grooming and response to stress inanimals. Oxytocin may also influence normal behavior in humans.Modulators of oxytocin binding to its receptors in the central nervoussystem may be useful in the prevention and treatment of disfunctions ofthe oxytocin system, including obsessive compulsive disorder (OCD) andother neuropsychiatric disorders (Kovacs et al.,Psychoneuroendocrinology 23, 945–962 (1998); McCarthy et al., U.K. Mol.Med. Today 3, 269–275 (1997); Bohus, Peptidergic Neuron, [Int Symp.Neurosecretion], 12^(th) (1996), 267–277, Publ. Birkhauser, Basel,Switz.; Leckman et al., Psychoneuroendocrinology 19, 723–749 (1994)).

Compounds which act as competitive inhibitors against vasopressinbinding to its receptors are useful in the treatment or prevention ofstate diseases involving vasopressin disorders in mammals, which includevasodilation and aquaresis (free-water diuresis), treating hypertensionand inhibiting platelet aggregation. They are useful in the treatment ofcongestive heart failure, cirrhosis with ascites, and in the syndrome ofinappropriate secretion of antidiuretic hormone (SIADH). Furthermore,vasopressin receptor antagonists have been found to be useful intreating disturbances or illnesses of the inner ear, particularly thoserelated to Meniere's disease (Zenner et al., WO 99/24051-A2 (1999)); andfor the prevention and treatment of ocular circulatory disorders,particularly intraocular hypertension or glaucoma and vision disorderssuch as shortsightedness (Ogawa et al., WO 99/38533-A1 (1999)).

SUMMARY OF THE INVENTION

This invention relates to novel compounds selected from those of Formula(I):

wherein:

-   R₁ and R₂ are, independently, selected from hydrogen, (C₁–C₆)lower    alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁–C₆)    lower alkylamino, (C₁–C₆) lower alkoxy, —OCF₃, (C₁–C₆) lower alkoxy    carbonyl, —NHCO[(C₁–C₆)lower alkyl], carboxy, —CONH₂, —CONH[(C₁–C₆)    lower alkyl], or —CON[(C₁–C₆) lower alkyl]₂;-   R₃ is a substituent selected from hydrogen, (C₁–C₆) lower alkyl,    (C₁–C₆) lower alkoxy, hydroxy, amino, (C₁–C₆) lower alkylamino, CO    lower alkyl (C₁–C₆), or halogen;-   R₄ is the moiety B–C; wherein:-   B is selected from the group of:

-   and C is selected from the group of:

wherein:

-   A is CH or N;-   R₅, R₆, R₇, R₈, R₉, R₁₀ are, independently, selected from hydrogen,    (C₁–C₆) lower alkyl, (C₁–C₆) lower alkoxy, (C₁–C₆) lower    alkylcarbonyl, (C₃–C₆) lower alkenyl, (C₃–C₆) lower alkynyl, (C₃–C₈)    cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, alkoxycarbonyl,    cycloalkyloxycarbonyl, aryl alkyloxycarbonyl, carbamoyl,    —O—CH₂—CH═CH₂, halogen, halo lower alkyl, trifluoromethyl, OCF₃,    S(lower alkyl), —OC(O)N[lower alkyl]₂, —CONH[lower alkyl],    —CON[lower alkyl]₂, lower alkylamino, di-lower alkylamino, lower    alkyl di-lower alkylamino, hydroxy, cyano, trifluoromethylthio,    nitro, amino, lower alkylsulfonyl, aminosulfonyl, lower    alkylaminosulfonyl,

-    phenyl or naphthyl;-   R₁₁ and R₁₂ are, independently, selected from the group of hydrogen,    (C₁–C₆) lower alkyl, (C₁–C₆) lower alkenyl, (C₃–C₆) lower alkynyl,    hydroxy (C₁–C₆) lower alkyl, alkoxy (C₁–C₆) lower alkyl, acyloxy    (C₁–C₆) lower alkyl, cyclo lower alkyl, or aryl, optionally    substituted by hydroxy, (C₁–C₆) lower alkoxy, halogen, cyano,    —SO₂[(C₁–C₆) lower alkyl, or —S[(C₁–C₆) lower alkyl];-   and R is selected from any of the following groups:

wherein:

-   R₁₃ is selected from hydrogen, (C₁–C₆) lower alkyl, cyanoethyl or

-   R₁₄ is selected from hydrogen or (C₁–C₆) lower alkyl;-   R₁₅ is one or two substituents selected from the group of hydrogen,    (C₁–C₆) lower alkyl, halogen, trifluoromethyl, (C₁–C₆) lower alkoxy,    (C₁–C₆) lower alkoxycarbonyl, or

-   R₁₆ represents one to two substituents selected from hydrogen, or    (C₁–C₆) lower alkyl;-   m is an integer from 0 to 2;-   n is an integer from 1 to 2;-   and p is an integer from 0 to 1;-   and the pharmaceutically acceptable salts, or pro-drug forms    thereof.

Among the more preferred compounds of this invention are those of theformula:

wherein:

-   R₁ and R₂ are, independently, selected from hydrogen, (C₁–C₆)lower    alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁–C₆)    lower alkylamino, (C₁–C₆) lower alkoxy, —OCF₃, (C₁–C₆) lower    alkoxycarbonyl, —NHCO[(C₁–C₆)lower alkyl], carboxy, —CONH₂, —CONH    (C₁–C₆) lower alkyl, or —CON[(C₁–C₆) lower alkyl]₂;-   R₃ is a substituent selected from hydrogen, (C₁–C₆) lower alkyl,    (C₁–C₆) lower alkoxy, hydroxy, amino, (C₁–C₆) lower alkylamino, —CO    lower alkyl (C₁–C₆), or halogen;-   R₄ is the moiety B–C; wherein:-   B is selected from the group of:

-   and C is selected from the group of:

-   R₅, R₆, R₇, R₈, R₉ and R₁₀ are independently, selected from H,    (C₁–C₆) lower alkyl, (C₁–C₆) lower alkoxy, hydroxy (C₁–C₆) lower    alkyl, alkoxy (C₁–C₆) lower alkyl, acyloxy (C₁–C₆) lower alkyl,    (C₁–C₆) lower alkylcarbonyl, (C₃–C₆) lower alkenyl, (C₃–C₆) lower    alkynyl, (C₃–C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy,    alkoxycarbonyl, cycloalkyloxycarbonyl, carbamoyl, —O—CH₂—CH═CH₂,    halogen, halo lower alkyl, trifluoromethyl, —OCF₃, —S(lower alkyl),    —OC(O)N[lower alkyl]₂, —CONH(lower alkyl), —CON[lower alkyl]₂, lower    alkylamino, di-lower alkylamino, lower alkyl di-lower alkylamino,    hydroxy, cyano, trifluoromethylthio, nitro, amino, lower    alkylsulfonyl, aminosulfonyl, or lower alkylaminosulfonyl;-   R₁₁ and R₁₂ are, independently, selected from the group of hydrogen,    (C₁–C₆) lower alkyl, (C₁–C₆) lower alkenyl, (C₃–C₆) lower alkynyl,    hydroxy (C₁–C₆) lower alkyl, alkoxy (C₁–C₆) lower alkyl, acyloxy    (C₁–C₆) lower alkyl, cyclo lower alkyl, or aryl, optionally    substituted by hydroxy, (C₁–C₆) lower alkoxy, halogen, cyano;-   R is selected from any of the following groups:

wherein:

-   R₁₃ is selected from the group of hydrogen, (C₁–C₆) lower alkyl, or    cyanoethyl;-   R₁₄ is selected from hydrogen or (C₁–C₆) lower alkyl;-   R₁₅ is one or two substituents selected, independently, from the    group of hydrogen, (C₁–C₆) lower alkyl, halogen, trifluoromethyl,    (C₁–C₆) lower alkoxy, (C₁–C₆) lower alkoxycarbonyl;-   R₁₆ and R_(16′) are selected independently from H, or (C₁–C₆) lower    alkyl;-   m is an integer from 0 to 2;-   n is an integer from 1 to 2;-   and p is an integer from 0 to 1;-   or a pharmaceutically acceptable salt or pro-drug form thereof.

As used herein the term “lower” in relation to alkoxy or alkyl isunderstood to refer to those groups having from 1 to 6 carbon atoms.Halogen refers to fluorine, chlorine, bromine or iodine.

It is understood by those practicing the art that some of the compoundsof this invention depending on the definition of R₁, R₂, R₃, R₄, R₅, R₆,R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ may contain one or more asymmetric centersand may thus give rise to enantiomers and diastereomers. The presentinvention includes all stereoisomers including individual diastereomersand resolved, enantiomerically pure R and S stereoisomers, as well asracemates, and all other mixtures of the R and S stereoisomers andpharmaceutically acceptable salts thereof, which possess the indicatedactivity. Optical isomers may be obtained in pure form by standardprocedures known to those skilled in the art. It is also understood thatthis invention encompasses all possible regioisomers, E-Z isomers,endo-exo isomers, and mixtures thereof which possess the indicatedactivity. Such isomers may be obtained in pure form by standardseparation procedures known to those skilled in the art. It isunderstood also by those practicing the art that some of the compoundsof this invention depending on the definition of R₄, R₅, R₆, R₈, R₉,R₁₀, R₁₁ and R₁₂ may be chiral due to hindered rotation, and give riseto atropisomers which can be resolved and obtained in pure form bystandard procedures known to those skilled in the art. Also included inthe present invention are all polymorphs and hydrates of the compoundsof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises the compounds described above, as wellas pharmaceutical compositions containing the compounds of thisinvention in combination or association with one or morepharmaceutically acceptable carrier or excipient. In particular, thepresent invention provides a pharmaceutical composition which comprisesa therapeutically effective amount of one or more compounds of thisinvention in a pharmaceutically acceptable carrier or excipient.

This invention also comprises methods for treating conditions in amammal, preferably a human, which are remedied or alleviated by oxytocinantagonist activity including, but not limited to, treatment orprevention of preterm labor, dysmenorrhea and suppressing labor prior tocaesarian delivery whenever desirable in a mammal, preferably in ahuman. The methods comprise administering to a mammal in need thereof atherapeutically effective but non-toxic amount of one or more of thecompounds of this invention.

The present invention also comprises combinations of the compounds ofthe present invention with one or more agents useful in the treatment ofdisorders such as preterm labor, dysmenorrhea, and stopping labor priorto caesarian delivery. More specifically, the compounds of the presentinvention may be effectively administered in combination with effectiveamounts of other tocolytic agents used in the treatment or prevention ofpreterm labor, dysmenorrhea or suppressing labor prior to caesareandelivery including β-adrenergic agonists, calcium channel blockers,prostaglandin synthesis inhibitors, other oxytocin antagonists (e.g.atosiban), magnesium sulfate, ethanol, and other agents useful in thetreatment of said disorders. The present invention is to be understoodas embracing all simultaneous or alternating treatments of anycombination of the compounds of the present invention with othertocolytic agents with any pharmaceutical composition useful for thetreatment of preterm labor, dysmenorrhea, and suppressing labor prior tocaesarean delivery in mammals.

The compositions are preferably adapted for intravenous (both bolus andinfusion) and oral administration. However, they may be adapted forother modes of administration including subcutaneous, intraperitoneal,or intramuscular administration to a human or a farm animal in need of atocolytic agent.

The compounds of the present invention can be used in the form of saltsderived from non toxic pharmaceutically acceptable acids or bases. Thesesalts include, but are not limited to, the following: salts withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and, as the case may be, such organicacids as acetic acid, oxalic acid, citric acid, tartaric acid, succinicacid, maleic acid, benzoic acid, benzene sulfonic acid, fumaric acid,malic acid, methane sulfonic acid, pamoic acid, and para-toluenesulfonic acid . Other salts include salts with alkali metals or alkalineearth metals, such as sodium, potassium, calcium or magnesium, or withorganic bases including quaternary ammonium salts. The compounds canalso be used in the form of esters, carbamates and other conventionalprodrug forms, which in general, will be functional derivatives of thecompounds of this invention which are readily converted to the activemoiety in vivo. This is meant to include the treatment of the variousconditions described hereinbefore with a compound of this invention orwith a compound which is not specifically disclosed but which convertsto a compound of this invention in vivo upon administration. Alsoincluded are metabolites of the compounds of the present inventiondefined as active species produced upon introduction of these compoundsinto a biological system.

When the compounds of this invention are employed for the aboveutilities, they may be combined with one or more pharmaceuticallyacceptable excipients or carriers, for example, solvents, diluents andthe like, and may be administered orally in such forms as tablets,capsules (including time release and sustained release formulations),pills, dispersible powders, granules, or suspensions containing, forexample, from 0.05 to 5% of suspending agent, syrups containing, forexample, from about 10 to 50% of sugar, and elixirs and the like, orparenterally in the form of sterile injectable solutions, suspensions oremulsions containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 25 to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

The effective dosage of active ingredients employed may vary dependingon the particular compound or salt employed, the mode of administration,age, weight, sex and medical condition of the patient, and the severityof the condition being treated. An ordinarily skilled physician,veterinarian or clinician can readily determine and prescribe theeffective amount of the agent required to prevent, counter or arrest theprogress of the condition. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydose of from about 0.5 to about 500 mg/Kg of mammal body weight,preferably given in divided doses two to four times a day, or in asustained release form. For most large mammals the total daily dosage isfrom about 0.5 to 100 mg, preferably from 0.5 to 80 mg/Kg. Dosage formssuitable for internal use comprise from about 0.05 to 500 mg of theactive compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier. This dosage regimen may be adjustedto provide the optimal therapeutic response. For example, severaldivided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, glycerol, non-ionic surfactants and edibleoils such as corn, peanut and sesame oils, as are appropriate to thenature of the active ingredient and the particular form ofadministration desired. Adjuvants customarily employed in thepreparation of pharmaceutical compositions may be advantageouslyincluded, such as flavoring agents, coloring agents, preserving agents,and antioxidants, for example vitamin E, ascorbic acid, BHT and BHA.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy injectability exists. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g. glycerol, propylene glycol, and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

Furthermore, active compounds of the present invention can beadministered intranasally using vehicles suitable for intranasaldelivery, or transdermally using transdermal skin patches known to thoseordinarily skilled in the art. When using a transdermal delivery system,the dosage administration will be continuous rather than in a single ordivided daily doses. The compounds of the present invention can also beadministered in the form of liposome delivery system wherein theliposomal lipid bilayers are formed from a variety of phospholipids.

Compounds of the present invention may also be delivered by the use ofcarriers such as monoclonal antibodies to which the active compounds arecoupled. The compounds of the present invention may also be coupled tosoluble polymers as drug carriers or to biodegradable polymers useful inachieving controlled release of the active agent.

Also according to the present invention there are provided processes forproducing the compounds of the present invention.

Process of the Invention

The compounds of the present invention may be prepared according to oneof the general processes outlined below.

The compounds of general formula (I) wherein R₄ consists of the moietyB–C, where B is selected from the group (a) or (b) and C is selectedfrom the group of (c), (d), (e) and (f) defined hereinbefore, can beconveniently prepared as shown in Scheme I.

According to the above preferred process, a tricyclic azepine of formula(1) wherein

R₃ and R₄ are defined hereinbefore, is reacted with perhaloalkanoylhalide preferable trichloroacetyl chloride in the presence of an organicbase such as N,N-diisopropylethyl amine (Hünig's base) in an aproticorganic solvent such as dichloromethane at temperatures ranging from−10° C. to ambient, to provide the desired trichloroacetyl intermediateof formula (2). Subsequent hydrolysis of (2) with aqueous base such assodium hydroxide, in an organic solvent such as tetrahydrofuran oracetone at temperatures ranging from −10° C. to ambient, yields theintermediate acid of formula (3). The required activation of thecarboxylic acid (3) for the subsequent coupling with a primary orsecondary amine of formula (5) can be accomplished in several ways.Thus, (3) can be converted to an acyl halide preferable a chloride orbromide of formula (4, J=COCl or COBr) by reaction with thionylchloride(bromide) or oxalyl chloride (bromide) or similar reagents knownin the art, either neat or in the presence of an inorganic base such aspotassium carbonate, or in the presence of an organic base such aspyridine, 4-(dimethylamino)pyridine, or a tertiary amine such astriethylamine in an aprotic solvent such as dichloromethane,N,N-dimethylformamide or tetrahydrofuran at temperatures ranging from−5° C. to 50° C. to yield the intermediate acylated derivative (4).Subsequent coupling of the acyl chloride(bromide) (4, J=COCl or COBr)with an appropriately substituted primary or secondary amine of formula(5) in the presence of a stoichiometric amount of Hünig's base, in anaprotic solvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran, at temperatures ranging from ambient to the refluxtemperature of the solvent, provides the desired compounds of formula(I) wherein

R, R₃ and R₄ are as defined hereinbefore.

Alternatively, the acylating species can be a mixed anhydride of thecorresponding carboxylic acid, such as that prepared by treating saidacid of formula (3) with 2,4,6-trichlorobenzoyl chloride in an aproticorganic solvent such as dichloromethane according to the procedure ofInanaga et al., Bull. Chem. Soc. Jpn. 52, 1989 (1979). Treatment of saidmixed anhydride of formula (4) with an appropriately substituted primaryor secondary amine of formula (5) in an aprotic solvent such asdichloromethane at temperatures ranging from ambient to the refluxtemperature of the solvent, provides the desired compounds of formula(I) wherein

R, R₃ and R₄ are as defined hereinbefore.

Alternatively, amidation of the carboxylic acids of formula (3) can beeffectively carried out by treatment of said acid with triphosgene in anaprotic solvent such as dichloromethane, followed by reaction of theactivated intermediate with an appropriately substituted primary orsecondary amine of formula (5) in the presence of an organic base suchas Hünig's base at temperatures ranging from −10° C. to ambient.

Another preferred process for the preparation of the compounds of thepresent invention of formula (I) wherein

R, R₃ and R₄ are as defined hereinbefore, consists of treating the acidof formula (3) with an activating reagent such asN,N-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride in thepresence of 1-hydroxybenzotriazole, followed by reaction of theactivated intermediate with an appropriately substituted primary orsecondary amine of formula (5), preferably in the presence of an organicbase such as Hünig's base and a catalytic amount of4-(dimethylamino)pyridine in an aprotic solvent such as dichloromethane,N,N-dimethylformamide or tetrahydrofuran at temperatures ranging from−10° C. to ambient.

In another preferred process, said acid (3) can be activated bytreatment with other activating agents such as N,N′-carbonyldiimidazolein an aprotic solvent such as dichloromethane or tetrahydrofuran, attemperatures ranging from −10° C. to the reflux temperature of thesolvent. Subsequent reaction of the intermediate activated imidazolidewith an appropriately substituted primary or secondary amine of formula(5) provides the desired compounds of formula (I) wherein

R, R₃ and R₄ are as defined hereinbefore.

Alternatively, the coupling of the appropriately substituted primary orsecondary amine of formula (5) with said acid of formula (3) can beeffectively carried out by using hydroxybenzotriazole tetramethyluroniumhexafluorophosphate as the coupling reagent in the presence of anorganic base such as Hünig's base and in a solvent such asN,N-dimethylformamide at temperatures ranging from −10° C. to ambient,to provide in good isolated yield and purity the desired compounds offormula (I) wherein

R, R₃ and R₄ are as defined hereinbefore.

Related coupling reagents such as diphenylphosphoryl azide, diethylcyano phosphonate, benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate and all other known in the literaturethat have been used in the formation of amide bonds in peptide synthesiscan also be used for the preparation of compounds of formula (I) wherein

R, R₃ and R₄ are as defined hereinbefore.

As an alternative, reaction of the intermediate 3-trihalomethylketone offormula (2) directly with an appropriately substituted primary orsecondary amine of formula (5) also provides the desired compounds offormula (I) wherein

R, R₃ and R₄ are as defined hereinbefore.

The method of choice for the preparation of compounds of formula (I)from the intermediate carboxylic acid (3) is ultimately chosen on thebasis of its compatibility with the R, R₃ and R₄ groups, and itsreactivity with the tricyclic diazepine of formula (1).

Another preferred process for the preparation of (I) of Scheme I isshown in Scheme II. A tricyclic diazepine of formula (1) is reacted withdiphosgene in an aprotic solvent such as dichloromethane, preferably inthe presence of an organic base such as triethylamine, followed byreaction of the resulting acylated intermediate with an appropriatelysubstituted primary or secondary amine of formula (5), to provide thedesired compounds of formula (I) wherein

R, R₃ and R₄ are as defined hereinbefore.

The tricyclic diazepines of formula (1) of Scheme I wherein R₄ isdefined hereinbefore, can be conveniently prepared as shown in SchemeIII.

Thus, a tricyclic diazepine of formula (6) is treated with anappropriately substituted acylating agent such as a haloaroyl halide,preferably an appropriately substituted acyl chloride(bromide) offormula (7, J=COCl or COBr) wherein R₄ is ultimately chosen on the basisof its compatibility with the present reaction scheme, in the presenceof an inorganic base such as potassium carbonate, or in the presence ofan organic base such as pyridine, 4-(dimethylamino)pyridine, or atertiary amine such as triethylamine or N,N-diisopropylethyl amine, inan aprotic solvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran, at temperatures ranging from −5° C. to 50° C. toprovide intermediates of general formula (1) wherein R₄ is definedhereinbefore.

Alternatively, the acylating species of formula (7) can be a mixedanhydride of the corresponding carboxylic acid, such as that prepared bytreating said acid with 2,4,6-trichlorobenzoyl chloride in an aproticorganic solvent such as dichloromethane according to the procedure ofInanaga et al., Bull. Chem. Soc. Jpn., 52, 1989 (1979). Treatment ofsaid mixed anhydride of general formula (7) with a tricyclic diazepineof formula (6) in a solvent such as dichloromethane, and in the presenceof an organic base such as 4-(dimethylaminopyridine), at temperaturesranging from 0° C. to the reflux temperature of the solvent, yields theintermediate acylated derivative (1) of Scheme III.

The acylating intermediate of formula (7) is ultimately chosen on thebasis of its compatibility with the R₄ groups, and its reactivity withthe tricyclic diazepine of formula (6).

The desired intermediates of formula (7) of Scheme III wherein R₄consists of the moiety B–C wherein B is (a) and C is (c) can beconveniently prepared by a process shown in Scheme IV. Thus, anappropriately substituted aryl(heteroaryl) iodide (bromide, chloride, ortrifluoromethane sulfonate) of formula (8, wherein P is a carboxylicacid protecting group, preferably P=alkyl or benzyl, M=I, Br, Cl, OTf)),and A, R₅, R₆ and R₇ are defined hereinbefore, is reacted with anaryl(heteroaryl) tri(alkyl)tin(IV) derivative of formula (9,W=Sn(trialkyl)₃, preferably Sn(n-Bu)₃) wherein A, R₈, R₉ and R₁₀ aredefined hereinbefore, in the presence of a Pd(0) catalyst, in thepresence or absence of inorganic salts (e.g. LiCl), to provide theintermediate ester (10). Subsequent unmasking of the carboxylic functionby hydrolysis, hydrogenolysis or similar methods known in the art,followed by activation of the intermediate acid (11) provides thedesired compounds of formula (19) wherein A, R₅, R₆, R₇, R₈, R₉ and R₁₀are hereinbefore defined, suitable for coupling with the tricyclicdiazepine of formula (6).

The desired intermediates of formula (7) of Scheme III wherein R₄consists of the moiety B–C where B is (a) and C is (d), (e) or (f), or Bis (b) and C is either (c), (d), (e) or (f), can be prepared by aprocess analogous to that exemplified in Scheme IV by replacingintermediates of formula (8 and 9) with appropriately substitutednaphthyl, quinolyl, pyrimidinyl or pyrazinyl intermediates.

Alternatively, the desired intermediates of formula (10) of Scheme IVwherein R₄ consists of the moiety B–C where B is (a) and C is (c), canbe prepared by coupling of the iodide(bromide, chloride,trifluoromethane sulfonate) (8, M=I, Br, Cl or OTf) and an appropriatelysubstituted aryl(heteroaryl)boron derivative of formula (9, preferablyW=B(OH)₂) in the presence of a palladium catalyst such as palladium(II)acetate or tetrakis(triphenylphosphine)palladium(0) and an organic basesuch as triethylamine or an inorganic base such as sodium(potassium orcesium) carbonate with or without added tetrabutylammoniumbromide(iodide), in a mixture of solvents such as toluene-ethanol-water,acetone-water, water or water-acetonitrile, at temperatures ranging fromambient to the reflux temperature of the solvent (Suzuki, Pure & Appl.Chem. 66, 213–222 (1994), Badone et al., J. Org. Chem. 62, 7170–7173(1997), Wolfe et al. J. Am. Chem. Soc. 121, 9559 (1999), Shen, Tetr.Letters 38, 5575 (1997)). The exact conditions for the Suzuki couplingof the halide and the boronic acid intermediates are chosen on the basisof the nature of the substrate and the substituents. Alternatively, thecoupling of (8, M=I or Br) with (9, A=N) can be carried out by using adialkylborane, preferably a diethylpyridoborane in the presence of aninorganic base such as potassium hydroxide and tetrabutylammoniumbromide(iodide), in an aprotic solvent such as tetrahydrofuran,according to the method of Ishikura et al., Synthesis 936–938 (1984).The desired intermediates of formula (10) of Scheme IV can be similarlyprepared from the bromide (8, M=Br) and the boronic acid (9) in asolvent such as dioxane in the presence of potassium phosphate and aPd(0) catalyst.

Alternatively, a cross-coupling reaction of an iodide (bromide, ortrifluoromethane sulfonate) of formula (9, W=Br, I or OTF) with abis(pinacolato)diboron [boronic acid, or trialkyltin(IV)] derivative offormula (8, M=

B(OH)₂, or SnBu₃) yields the desired intermediate of formula (10) whichis converted to (I) in the manner of Scheme IV.

The desired intermediates of formula (10) of Scheme IV wherein R₄consists of the moiety B–C wherein B is (a) and C is (d), (e) or (f), orB is (b) and C is either (c), (d), (e) or (f), can be prepared inanalogous fashion by replacing intermediates of formulas (8 and 9) withappropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinylintermediates.

The required appropriately substituted aryl(heteroaryl) halides offormula (8, M=Br or I) of Scheme IV are either available commercially,or are known in the art, or can be readily accessed in quantitativeyields and high purity by diazotization of the corresponding substitutedanilines (8, P=H, alkyl or benzyl, M=NH₂) followed by reaction of theintermediate diazonium salt with iodine and potassium iodide in aqueousacidic medium essentially according to the procedures of Street et al,.J. Med. Chem. 36, 1529 (1993) and Coffen et al., J. Org. Chem. 49, 296(1984) or with copper(I) bromide, respectively (March, Advanced OrganicChemistry, 3^(rd) Edn., p.647–648, John Wiley & Sons, New York (1985)).

Alternatively, the desired intermediates of formula (11, A=CH) of SchemeIV wherein R₄ consists of the moiety B–C wherein B is (a, A=CH) and C is(c, A=CH) can be conveniently prepared as shown in Scheme V bycross-coupling reaction of an appropriately substituted pinacolatoborane of formula (13, A=CH) wherein R₈, R₉ and R₁₀ are hereinbeforedefined, with an aryl triflate of formula (14, Y=OTf) or an aryl halide(14, Y=Br, I) wherein R₅, R₆ and R₇ are defined hereinbefore, accordingto the general procedures of Ishiyama et al., Tetr. Lett. 38, 3447–3450(1997) and Giroux et al. Tetr. Lett. 38, 3841–3844 (1997), followed bybasic or acidic hydrolysis of the intermediate nitrile of formula (15)(cf. March, Advanced Organic Chemistry, 3^(rd) Edn., John Wiley & Sons,New York, p. 788 (1985)).

Alternatively, reaction of an iodide (bromide, or trifluoromethanesulfonate) of formula (12, X=Br, I, or OTf) with abis(pinacolato)diboron [boronic acid or trialkyl tin(IV)] derivative offormula (14, Y=

B(OH)₂, or SnBu₃) yields the desired intermediate of formula (15) whichis converted to (6) in the manner of Scheme V.

The desired intermediates of formula (11) of Scheme IV can be preparedin analogous fashion by replacing intermediates of formulas (13 and 14)with appropriately substituted naphthyl intermediates.

The desired phenyl boronic esters of formula (13) of Scheme V can beconveniently prepared by the palladium-catalyzed cross-coupling reactionof the pinacol ester of diboronic acid (16) with an appropriatelysubstituted aryl halide preferably a bromide or iodide (12, X=Br, I) oraryl triflate (12, X=OTf) according to the described procedures ofIshiyama et al., J. Org. Chem. 60, 7508–7510 (1995) and Giroux et al.,Tetr. Lett. 38, 3841–3844 (1997).

The desired compounds of formula (1) of Scheme IV wherein R₄ consists ofthe moiety B–C wherein B is (a) and C is (c) can be alternativelyprepared by a process shown in Scheme VI.

Thus, a tricyclic diazepine of formula (6) is treated with anappropriately substituted acylating agent such as a haloaroyl(heteroaroyl)halide, preferably aniodo(bromo)aroyl(heteroaroyl)chloride(bromide) of formula (17, J=COCl orCOBr; X=I, Br) wherein R₅, R₆ and R₇ are hereinbefore defined, using anyof the procedures hereinbefore described, to provide the acylatedintermediate of general formula (18) of Scheme VI.

Alternatively, the acylating species of formula (17) can be a mixedanhydride of the corresponding carboxylic acid. Treatment of said mixedanhydride of general formula (17) with a tricyclic diazepine of formula(6) according to the procedure described hereinbefore yields theintermediate acylated derivative (18).

The acylating intermediate of formula (17) is ultimately chosen on thebasis of its compatibility with A and the R₅, R₆ and R₇ groups, and itsreactivity with the tricyclic diazepine of formula (6).

A Stille coupling reaction of (18, X=I) with an appropriatelysubstituted organotin reagent such as a trialkyltin(IV) derivative,preferably a tri-n-butyltin(IV) derivative of formula (9, W=SnBu₃) whereA, R₈, R₉ and R₁₀ are hereinbefore defined, in the presence of acatalyst such as tetrakis(triphenylphosphine)palladium(0), in an aproticorganic solvent such as toluene and N,N-dimethylformamide, attemperatures ranging from ambient to 150° C. (cf. Farina et al., J. Org.Chem, 59, 5905 (1994) and references cited therein, affords the desiredcompounds of formula (1) wherein

A, R₃, R₅, R₆, R₇, R₈, R₉ and R₁₀ are as defined hereinbefore.

Alternatively, reaction of a compound of formula (18, X=Cl, Br or I)with an appropriately substituted aryl(heteroaryl)boronic acid offormula (9, W=B(OH)₂) wherein A, R₅, R₆, R₇, R₈, R₉ and R₁₀ arehereinbefore defined, in a mixture of solvents such astoluene-ethanol-water, and in the presence of a Pd(0) catalyst and abase such as sodium carbonate, at temperatures ranging from ambient tothe reflux temperature of the solvent, yields the desired compounds offormula (1) wherein

A, R₃, R₅, R₆, R₇, R₈, R₉ and R₁₀ are as defined hereinbefore.

The preferred substituted aroyl(heteroaroyl) chlorides(bromides) offormula (17) of Scheme VI (X=I, Br; J=COCl or COBr) wherein A, R₅, R₆and R₇ are as defined hereinbefore, are either available commercially,or are known in the art, or can be readily prepared by proceduresanalogous to those in the literature for the known compounds.

The intermediates of formula (9, W=Sn(alkyl)₃, alkyl=n-butyl) of SchemeVI are either commercially available, or can be conveniently prepared asshown in Scheme VII from the corresponding bromo starting materials offormula (20) wherein A, R₈, R₉, and R₁₀ are hereinbefore defined, byfirst reacting them with n-butyl lithium followed by reaction of theintermediate lithiated species with a trialkyl (preferably trimethyl ortri-n-butyl)tin(IV) chloride.

The preferred substituted aryl(heteroaryl)boronic acids of formula (9,W=B(OH)₂) are either available commercially, or are known in the art, orcan be readily prepared by procedures analogous to those in theliterature for the known compounds.

The desired compounds of formula (1) of Scheme VI wherein R₄ consists ofthe moiety B–C wherein B is (a) and C is (d), (e) or (f), or B is (b)and C is either (c), (d), (e) or (f) can be prepared in analogousfashion by replacing intermediates of formulas (17 and 9) withappropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinylintermediates.

Alternatively, as shown in Scheme VIII, the appropriately substitutedaroyl(heteroaroyl) halides, preferably aroyl(heteroaroyl)chlorides offormula (21, J=COCl) where A, R₅, R₆ and R₇ are hereinbefore defined,are reacted with a tricyclic diazepine of formula (6) to provide theintermediate bromides of formula (22). Subsequent reaction of (22) withan hexa alkyl-di-tin (preferably hexa-n-butyl-di-tin(IV)) in thepresence of a Pd(0) catalyst such astetrakis(tri-phenylphosphine)palladium(0) and lithium chloride, providesthe stannane intermediate of formula (23). Further reaction of thetri-n-butyl tin(IV) derivative (23) with the appropriately substitutedaryl(heteroaryl) halide of formula (24, M=bromo or iodo) wherein A, R₈,R₉, and R₁₀ are hereinbefore defined, in the presence of a Pd(0)catalyst such as tetrakis(triphenylphosphine) palladium(0), yields thedesired compounds of formula (1) wherein R₄ consists of the moiety B–Cwherein B is (a) and C is (c), and

A, R₅, R₆, R₇, R₈, R₉ and R₁₀ are defined hereinbefore.

The desired compounds of formula (1) of Scheme VIII wherein R₄ consistsof the moiety B–C wherein B is (a) or (b) and C is (d), (e) or (f) canbe prepared in analogous fashion by replacing intermediates of formulas(21 and 24) with appropriately substituted naphthyl, quinolyl,pyrimidinyl or pyrazinyl intermediates.

Alternatively, the desired compounds of formula (1) of Scheme VIIIwherein R₄ consists of the moiety B–C wherein B is (a, A=CH), and C is(c, A=CH) can be prepared as shown in Scheme IX.

Thus, an appropriately substituted biphenyl of formula (43) wherein R₅,R₆, and R₇ are defined hereinbefore, is treated with carbon monoxide inthe presence of a tricyclic diazepine of formula (6), a palladium(0)catalyst preferably PdBr₂(Ph₃P)₂ and a tertiary amine preferablyn-tributylamine, in a solvent such as anisole or dioxane, attemperatures ranging from ambient to the reflux temperature of thesolvent (cf. Schoenberg et al. J. Org. Chem. 39, 3327 (1974)) to providethe desired compounds of formula (1) wherein A is CH, and

R₃, R₅, R₆, R₇, R₈, R₉ and R₁₀ are defined hereinbefore.

In analogous fashion one can prepare compounds of formula (1) of SchemeIX wherein R₄ consists of the moiety B–C wherein B is (b) and C is (c,A=CH) or (d, A=CH) provided that the intermediates of formula (43) arereplaced by the appropriately substituted phenyl or naphthylintermediates.

A preferred process for the preparation of the compounds of formula (1)of Scheme I wherein

A, R₃, R₅, R₆ and R₇ are defined hereinbefore, and R₄ consists of themoiety B–C wherein B is (a) and C is (g) defined hereinbefore, is shownin Scheme X.

Thus, an appropriately substituted aroyl(heteroaroyl)halide preferablyan aroyl(heteroaroyl)chloride of formula (25, J=COCl) is reacted with atricyclic diazepine of formula (6) in the presence of a base such aspyridine, or a tertiary amine such as triethylamine orN,N-diisopropylethyl amine, in an aprotic organic solvent such asdichloromethane or tetrahydrofuran, at temperatures from −40° C. to 50°C. to provide the acylated intermediate of formula (26). Alternatively,the acylating species can be a mixed anhydride under the reactionconditions described hereinbefore. Subsequent reduction of (26) ispreferably effected under conditions of catalytic reduction (i.e.hydrogen, Pd on charcoal), transfer hydrogenation (i.e.hydrazine/ethanol/Pd on charcoal) or under chemical reduction conditions(i.e. with tin(II)chloride dihydrate in a protic organic solvent such asethanol, zinc in acetic acid) or related reduction conditions known inthe art, to yield the desired aniline of formula (27). The exactconditions for the conversion of the nitro to amino group are chosen onthe basis of compatibility with the preservation of other functionalgroups in the molecule. Condensation of (27) with a 1,4-diketone offormula (28) in an aprotic organic solvent such as benzene or toluene,in the presence of acetic acid or a catalytic amount ofp-toluenesulfonic acid with concomitant removal of water, attemperatures ranging from ambient to reflux temperature of the solventaccording to the general procedure of Bruekelman et al., J. Chem. Soc.Perkin Trans. I, 2801–2807 (1984) provides the desired compounds offormula (1) wherein R₄ consists of the moiety B–C wherein B is (a) and Cis (g), and

A, R₃, R₅, R₆, R₇, R₁₁ and R₁₂ are defined hereinbefore.

The desired compounds of formula (1) of Scheme X wherein R₄ consists ofthe moiety B–C wherein B is (b) and C is (g) can be prepared inanalogous fashion by replacing the intermediate of formula (25) with anappropriately substituted naphthyl.

Alternatively, the desired compounds of formula (1) of Scheme X can beprepared as shown in Scheme XI.

According to this process an aryl(heteroaryl)nitrile of formula (29) iscondensed with a 1,4-diketone of formula (28) in an aprotic organicsolvent such as benzene or toluene, in the presence of acetic acid or acatalytic amount of p-toluene sulfonic acid with concomitant removal ofwater, at temperatures ranging from ambient to reflux temperature of thesolvent according to the general procedure of Bruekelman et al., J.Chem. Soc. Perkin Trans. I, 2801–2807 (1984) to yield the intermediatepyrrole of formula (30). Subsequent hydrolysis of the nitrile (30) tothe carboxylic acid of formula (31) is efficiently accomplished bytreatment of (30) with aqueous base (cf. March, Advanced OrganicChemistry, 3^(rd) Edn., John Wiley & Sons, New York, p. 788 (1985)).Subsequent conversion of the acid (31) into an acylating species,preferably an acid chloride(bromide) of formula (32, J=COCl or COBr) ora mixed anhydride is accomplished by procedures analogous to thosedescribed hereinbefore. The acylating agent (32) is used to acylate atricyclic diazepine of formula (6) to provide the desired compounds offormula (1) wherein

A and R₃ are defined hereinbefore, and R₄ consists of the moiety B–Cwherein B is (a) and C is the moiety (g) defined hereinbefore.

The compounds of formula (1) of Scheme XI wherein R₄ consists of themoiety B–C wherein B is (b) and C is (g) defined hereinbefore can beprepared in analogous fashion by replacing the intermediates of formula(29) with an appropriately substituted naphthyl.

A preferred process for the preparation of the desired compounds ofgeneral formula (I) of Scheme I wherein R₄ consists of the moiety B–C,where B is selected from the group (a) and C is selected from the group(g) defined hereinbefore is shown in Scheme XII.

Thus, a tricyclic diazepine of formula (33) wherein

and R₃ are defined hereinbefore, carrying a protecting group such afluorenylalkoxycarbonyl group, preferably a fluorenylmethyloxycarbonyl(P=Fmoc) group, or an alkoxycarbonyl protecting group preferably atert-butyloxycarbonyl (P=Boc) group is reacted with a perhaloalkanoylhalide preferably trichloroacetyl chloride, in the presence of anorganic base such as N,N-diisopropylethyl amine (Hünig's base) or atertiary amine such as triethylamine, optionally in the presence ofcatalytic amounts of 4-(dimethylamino)pyridine, in an aprotic organicsolvent such as dichloromethane, at temperatures ranging from −10° C. toambient to provide the desired trichloroacetyl intermediate of formula(34). Subsequent hydrolysis of the trichloroacetyl group with aqueousbase such as sodium hydroxide in an organic solvent such as acetone, attemperatures ranging from −10° C. to ambient, is accompanied bysimultaneous removal of the protecting group and yields the intermediateacid of formula (35). The required amidation of the carboxylic acid (35)can be effectively accomplished by treating (35) with an activatingreagent such as N,N-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride in thepresence of 1-hydroxybenzotriazole, followed by reaction of theactivated intermediate with an appropriately substituted primary orsecondary amine of formula (5) preferably in the presence of Hünig'sbase or a catalytic amount of 4-(dimethylamino)pyridine, in an aproticsolvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran, at temperatures ranging from −10° C. to ambient.

Other coupling reagents known in the literature that have been used inthe formation of amide bonds in peptide synthesis can also be used forthe preparation of compounds of formula (36) wherein

R and R₃ are as defined hereinbefore. The method of choice for thepreparation of compounds of formula (36) from the intermediatecarboxylic acid (35) is ultimately chosen on the basis of itscompatibility with the

and R₃ groups, and its reactivity with the tricyclic diazepine offormula (6). Subsequent reaction of a tricyclic diazepine amide (36)with an acylating agent of formula (32) of Scheme XI provides thedesired compounds of formula (I) wherein

A and R₃ are defined hereinbefore, R₄ consists of the moiety B–C whereinB is (a) and C is the moiety (g) defined hereinbefore.

The preferred compounds of formula (I) of Scheme I wherein R₄ consistsof the moiety B–C wherein B is (b) and C is the moiety (g) definedhereinbefore, can be prepared in analogous fashion by replacing theintermediate of formula (32) of Scheme XII with an appropriatelysubstituted naphthyl intermediate.

Preferred processes for the preparation of compounds of formula (I) ofScheme I wherein R₄ consists of the moiety B–C wherein B is (a) or (b)and C is (d), (e) or (f) and

A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore, alsoutilize acylation of the amide intermediate (36) of Scheme XII with anacylating agent of formula (19) of Scheme IV.

An alternate preferred process for the preparation of the compounds offormula (I) of Scheme I wherein R₄ consists of the moiety B–C wherein Bis (a) and C is (g) defined hereinbefore, is shown in Scheme XIII.

According to the above process a substituted tricyclic diazepine offormula (37) wherein

A, R₃, R₅, R₆ and R₇ are defined hereinbefore, carrying a protectinggroup such a fluorenylalkoxycarbonyl group, preferably afluorenylmethyloxycarbonyl (P=Fmoc) group is reacted with aperhaloalkanoyl halide preferably trichloroacetyl chloride in thepresence of an organic base such as N,N-diisopropylethyl amine (Hünig'sbase) or a tertiary amine such as triethylamine, in an aprotic organicsolvent such as dichloromethane, at temperatures ranging from −10° C. toambient, to provide the desired trichloroacetyl intermediate of formula(38). Subsequent deprotection of (38) is carried out by treatment with asolution of an organic base preferably piperidine, in an organic solventsuch as N,N-dimethylformamide, at ambient temperature to provide thedesired aniline (44). Condensation of (44) with a 1,4-diketone offormula (28) either neat or in an aprotic organic solvent such asbenzene or toluene, in the presence of a catalytic amount of acarboxylic acid preferably p-toluene sulfonic acid or acetic acid withconcomitant removal of water, at temperatures ranging from ambient to100° C. or to the reflux temperature of the solvent according to thegeneral procedure of Bruekelman et al., J. Chem. Soc. Perkin Trans. I,2801–2807 (1984), provides the desired intermediate of formula (45).Subsequent hydrolysis of the trichloroacetyl group with aqueous basesuch as sodium hydroxide, in an organic solvent such as acetone ortetrahydrofuran, at temperatures ranging from −10° C. to the refluxtemperature of the solvent, yields the intermediate carboxylic acid offormula (46). Subsequent amidation provides the desired compounds offormula (I) wherein R₄ consists of the moiety B–C wherein B is (a) and Cis (g), and

A, R₃, R₅, R₆, R₇, R₁₁ and R₁₂ are defined hereinbefore,

The required amidation of (46) can be effectively accomplished bytreating said carboxylic acid with an activating reagent such asN,N-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride in thepresence of 1-hydroxybenzotriazole, followed by reaction of theactivated intermediate with an appropriately substituted primary orsecondary amine of formula (5), preferably in the presence of Hünig'sbase or a catalytic amount of 4-(dimethylamino)pyridine, in an aproticsolvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran, at temperatures ranging from −10° C. to ambient. Othercoupling reagents known in the literature that have been used in theformation of amide bonds in peptide synthesis can also be used for thepreparation of compounds of formula (I) wherein R₄ consists of themoiety B–C wherein B is (a) and C is (g), and

A, R₃, R₅, R₆, R₇, R₁₁ and R₁₂ are defined hereinbefore. The method ofchoice for the preparation of compounds of formula (I) from theintermediate carboxylic acid (46) is ultimately chosen on the basis ofits compatibility with the

and R₃ groups, and its reactivity with the tricyclic diazepine offormula (6).

The desired compounds of formula (I) of Scheme XIII wherein R₄ consistsof the moiety B–C wherein B is (b) and C is (g) can be prepared inanalogous fashion by replacing the intermediate of formula (27) with anappropriately substituted naphthyl intermediate.

Alternatively, the intermediate acids of formula (35) of Scheme XIIwherein

and R₃ are defined hereinbefore, can be obtained by reacting a tricyclicdiazepine of formula (6) with an excess of acylating agent preferablytrifluoroacetic anhydride or trichloroacetyl chloride in the presence ofan inorganic base such as potassium carbonate or an organic base such asN,N-diisopropylethylamine, in an aprotic solvent such asN,N-dimethylformamide, followed by basic hydrolysis of the intermediatebis-trifluoroacetyl(trichloroacetyl) intermediate of formula (39 X=F orCl) preferably with aqueous sodium hydroxide in a protic organic solventsuch as ethano, at temperatures ranging from ambient to the refluxtemperature of the solvent as exemplified in Scheme XIV.

Preferred processes for the preparation of compounds of formula (I) ofScheme I wherein R₄ consists of the moiety B–C wherein B is (a) or (b)and C is (d), (e) or (f) and

A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore, alsoutilize acylation of the amide intermediate (36) of Scheme XII with anacylating agent of formula (17) of Scheme IV, as shown in Scheme XV.

Alternatively, the preferred compounds of formula (I) of Scheme Iwherein R₄ consists of the moiety B–C wherein B is (a) and C is (c) and

A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore, can beprepared by acylation of the amide intermediate (36) of Scheme XII withan acylating agent of formula (21) of Scheme VIII, as shown in SchemeXVI.

Alternatively, the preferred compounds of formula (I) of Scheme (I)wherein R₄ consists of the moiety B–C wherein B is (a) and C is (c) and

A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore, can beprepared by acylation of the amide intermediate (36) of Scheme XII withan acylating agent of formula (19) of Scheme IV, wherein J ishereinbefore defined, as shown in Scheme XVII.

The subject compounds of the present invention were tested forbiological activity according to the following procedures.

Vasopressin Binding in Chinese Hamster Ovary Cell Membranes ExpressingHuman Vasopressin V_(1a) Subtype Receptors

Receptor Source:

Chinese hamster ovary cells (CHO cells) stably transfected with thehuman vasopressin V_(1a) subtype receptors were either obtained fromBioSignal Inc., 1744 rue Williams, Montreal, Quebec, Canada or obtainedfrom M. Thibonnier, Case Western Reserve University School of Medicine,Cleveland, Ohio.

A. Passaging and Amplification of Cells:

CHO cells transfected with the human vasopressin V_(1a) subtypereceptors obtained from M. Thibonnier (pZeoSV vector) are allowed togrow to confluency (approx. >90%) in T-150 flasks under sterileconditions, in a cell culture medium of F-12 Nutrient Mixture (HAM) withL-glutamine (Gibco Cat. # 11765-054) containing 15 mM HEPES (Gibco Cat.# 15630-080), 1% antibiotic/antimycotic (add 5 mL 100×, Gibco Cat. #15240-062 per 500 mL F-12), 250 μg/mL Zeocin (add 1.25 mL of 100 mg/mLInvitrogen R-250-01 per 500 mL F-12) and 10% Fetal Bovine Serum(Qualified, heat inactivated, Gibco Cat. # 16140-063). The medium isremoved by aspiration and the cells are washed with 10 mL of Hank'sBalanced Salt solution (Gibco Cat. # 14175-095). The salt solution isremoved by aspiration and the cells are trypsinized with 5 mL oftrypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na, Gibco Cat. # 25300-070)for 1 min. The trypsin is removed by aspiration and the cells dislodgedby tapping. Cell Culture medium (e.g. 30 mL for 1:30 split) isimmediately added and mixed well to inactivate trypsin. 1 mL of detachedcells is added to new culture flasks containing fresh cell culturemedium (e.g., into 25 mL per T-150 flask), and mixed gently. The cellsare incubated at 37° C. in 5% CO₂. The medium is changed at 3 to 4 daysinterval (or as appropriate). The cells grow to confluency(approx. >75%–95%) within 7–8 days. All steps are done under sterileconditions.

B. Membrane Preparation:

The cells are washed twice gently with Hank's Balanced Salt solution(e.g,. use 10 mL per T-150 flask). The excess is removed and the cellsare bathed for 15–30 min. in an enzyme-free Cell Dissociation Buffer(e.g. use 8 mL Hank's Based, Gibco Cat. # 13150-016 per T-150 flask)until the cells are loosened. The contents are transferred to centrifugetubes (50 mL) kept in an ice bath. All subsequent steps are done at 4°C. The tubes are centrifuged at 300×g for 15 min (1380 rpm on SORVAL,Model RT6000D, using the rotor for 50 mL tubes). The supernatant isdiscarded and the cells suspended in homogenizing buffer(10 mM Tris-HClcontaining 0.25 M sucrose and 1 mM EDTA, pH 7.4) ensuring that thevolume of the buffer is about ten times the volume of the cell pellet.The cells are pooled into a centrifuge tube (50 mL) and homogenized withPolytron at setting 6 for 10 sec. The homogenate is transferred into aPotter-Elvjehm homogenizer and homogenized with 3 strokes. Thehomogenate is centrifuged at 1500×g for 10 min at 4° C. (3100 rpm usingSORVAL, model RT6000D, using the rotor for 50 mL tubes). The pellet isdiscarded. The supernatant is centrifuged at 100,000×g for 60 min. at 4°C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpm with rotor type70 Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15 mL tubes; or35,800 rpm with rotor type 45Ti). The supernantant is discarded and thepellet suspended in 3 to 4 mL of Tris buffer (50 mM TRIS-HCl, pH 7.4).The protein content is estimated by the Bradford or Lowry method. Thevolume of the membrane suspension is adjusted with the membrane buffer(50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) to give 3.0 mg/mL(or as appropriate) of protein. The membranes are aliquoted and storedat −70° C.

C. Radioligand Binding Assay:

In wells of a 96-well format microtiter plate, is added 90, 110 or 130μL (to make up a final volume of 200 μL) of assay buffer containing 50mM of Tris-HCl (pH 7.4), BSA (heat inactivated, protease-free), 0.1% of5 mM MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin, 2 mg %1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF. Theinhibitors are added on the day of the experiment. The components aremixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4. To each well is added 20 μL of unlabeledManning ligand (to give a final concentration of 0.1 to 10 nM forstandard curve and 1000 nM for non specific binding) or test compoundsin 50% DMSO (e.g. for final concentrations of 0.1 to 1000 nM or asappropriate) or 50% DMSO as vehicle control. 20 μL of 50% DMSO is addedfor Manning and other peptide ligands and the assay buffer volume isadjusted accordingly. To each well is added 50 μL of frozen membranesuspension thawed immediately prior to use and diluted in the assaybuffer to the required concentration (equivalent to 25 to 50 μg ofprotein/well as needed). 20 μL of 8 nM [³H]Manning ligand in the assaybuffer, prepared just before use, is added, and incubated at roomtemperature for 60 min. shaking the plate on a mechanical shaker for thefirst 15 min. The incubation is stopped by rapid filtration of the theplate contents followed by wash with ice-cold buffer (50 mM Tris-HCl, pH7.4) using a cell harvester (Tomtek and Printed filtermat-B filterpaper). The filter paper is thoroughly dried (7–12 min. in a microwaveoven) and impregnated with MeltiLex B/H melt-on scintillation wax sheetsand the radioactivity counted in a betaplate scintillation counter.

Vasopressin Binding in Chinese Hamster Ovary Cell Membranes ExpressingHuman Vasopressin V₂ Subtype Receptors

Receptor Source:

Chinese Hamster Ovary (CHO) cells stably transfected with the human V₂subtype receptors were obtained from M. Thibonnier, Case Western ReserveUniversity School of Medicine, Cleveland, Ohio.

A. Passaging and Amplification of Cells:

CHO cells transfected with the human vasopressin V₂ subtype receptorsobtained from M. Thibonnier (pZeoSV vector) are allowed to grow toconfluency (approx. >90%) in T-150 flasks under sterile conditions, in acell culture medium of F-12 Nutrient Mixture (HAM) with L-glutamine(Gibco Cat. # 11765-054) containing 15 mM HEPES (Gibco Cat. #15630-080), 1% antibiotic/antimycotic (add 5 mL 100×, Gibco Cat. #15240-062 per 500 mL F-12), 250 μg/mL Zeocin (add 1.25 mL of 100 mg/mLInvitrogen R-250-01 per 500 mL F-12) and 10% Fetal Bovine Serum(Qualified, heat inactivated, Gibco Cat. # 16140-063). The medium isremoved by aspiration and the cells washed with 10 mL of Hank's BalancedSalt solution (Gibco Cat. # 14175-095). The salt solution is removed byaspiration and the cells trypsinized with 5 mL of trypsin-EDTA (0.05%trypsin, 0.53 mM EDTA-4Na, Gibco Cat. # 25300-070) for 1 min. Thetrypsin is removed by aspiration and the cells dislodged by tapping.Cell Culture medium (e.g. 30 mL for 1:30 split) is immediately added andmixed well to inactivate trypsin. 1 mL of detached cells is added to newculture flasks containing fresh Cell Culture medium (e.g. into 25 mL perT-150 flask), and mixed gently. The cells are incubated at 37° C. in 5%CO₂. The medium is changed at 3 to 4 day interval (or as appropriate).The cells grow to confluency (approx. >75%–95%) within 7–8 days. Allsteps are done under sterile conditions.

B. Membrane Preparation:

The cells are washed twice gently with Hank's Balanced Salt solution(e.g. use 10 mL per T-150 flask). The excess solution is removed and thecells bathed for 15–30 min. in an enzyme-free Cell Dissociation Buffer(e.g. use 8 mL Hank's Based, Gibco Cat. # 13150-016 per T-150 flask)until cells are loosened. The contents are transferred to centrifugetubes (50 mL) kept in ice bath. All subsequent steps are done at 4° C.The tubes are centrifuged at 300×g for 15 min (1380 rpm on SORVAL, ModelRT6000D, using the rotor for 50 mL tubes). The supernatant is discardedand the cells suspended in homogenizing buffer(10 mM Tris-HCl containing0.25 M sucrose and 1 mM EDTA, pH 7.4) ensuring that the volume of thebuffer is about ten times the volume of the cell pellet. The cells arepooled into a centrifuge tube (50 mL) and homogenized with Polytron atsetting 6 for 10 sec. The homogenate is transferred into aPotter-Elvjehm homogenizer and homogenized with 3 strokes. Thehomogenate is centrifuged at 1500×g for 60 min at 4° C. (3100 rpm usingSORVAL, model RT6000D, using the rotor for 50 mL tubes). The pellet isdiscarded. The supernatant is centrifuged at 100,000×g for 60 min. at 4°C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpm with rotor type70 Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15 mL tubes; or35,800 rpm with rotor type 45Ti). The supernantant is discarded and thepellet suspended in 3 to 4 mL of Tris buffer (50 mM TRIS-HCl, pH 7.4).The protein content is estimated by the Bradford or Lowry method. Thevolume of the membrane suspension is adjusted with the membrane buffer(50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) to give 3.0 mg/mL(or as appropriate) of protein. The membranes are aliquoted and storedat −70° C.

C. Radioligand Binding Assay:

In wells of a 96-well format microtiter plate, is added 90, 110 or 130μL (to make up a final volume of 200 μL) of assay buffer containing 50mM of Tris-HCl (pH 7.4), BSA (heat inactivated, protease-free), 5 mM of0.1% MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin, 2 mg %1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF. Theinhibitors are added on the day of the experiment. The components aremixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4. To each well is added 20 μL of unlabeledarginine vasopressin (AVP) (to give a final concentration of 0.1 to 10nM for standard curve and 1000 nM for non specific binding) or testcompounds in 50% DMSO (e.g. for final concentrations of 0.1 to 1000 nMor as appropriate) or 50% DMSO as vehicle control. For vasopressin andother peptide ligands 20 μL of 50% DMSO is added and the assay buffervolume is adjusted accordingly. To each well is added 50 μL of frozenmembrane suspension thawed immediately prior to use and diluted in assaybuffer to the required concentration (equivalent to 25 to 50 μg ofprotein/well as needed). 20 μL of 8 nM [³H]arginine vasopressin ligandin the assay buffer, prepared just before use is added and incubated atroom temperature for 60 min. shaking the plate on a mechanical shakerfor the first 15 min. The incubation is stopped by rapid filtration ofthe plate contents followed by wash with ice-cold buffer (50 mMTris-HCl, pH 7.4) using a cell harvester (Tomtek and Printed filtermat-Bfilter paper). The filter paper is thoroughly dried (7–12 min. in amicrowave oven) and impregnated with MeltiLex B/H melt-on scintillationwax sheets and the radioactivity counted in a betaplate scintillationcounter.

Oxytocin Binding in Chinese Hamster Ovary Cell Membranes ExpressingHuman Oxytocin Receptors

Receptor Source:

Chinese Hamster Ovary (CHO) cells stably transfected with the humanoxytocin receptor (cf. Tanizawa et al., U.S. Pat. No. 5,466,584 (1995)to Rohto Pharmaceutical Co. Ltd., Osaka, Japan) were obtained from M.Thibonnier, Case Western Reserve University School of Medicine,Cleveland, Ohio.

A. Passaging and Amplification of Cells:

CHO cells transfected with the human oxytocin receptors obtained from M.Thibonnier (pcDNA3.1 vector) are allowed to grow to confluency(approx. >90%) in T-150 flasks under sterile conditions, in a cellculture medium of F-12 Nutrient Mixture (HAM) with L-glutamine (GibcoCat. # 11765-054) containing 15 mM HEPES (Gibco Cat. # 15630-080), 1%antibiotic/antimycotic (add 5 mL 100×, Gibco Cat. # 15240-062 per 500 mLF-12), 400 μg/mL of Geneticin (add 4 mL of 50 mg/mL per 500 mL F-12) and10% Fetal Bovine Serum (Qualified, heat inactivated, Gibco Cat. #16140-063). The medium is removed by aspiration and the cells are washedwith 10 mL of Hank's Balanced Salt solution (Gibco Cat. # 14175-095).The salt solution is removed by aspiration and the cells trypsinizedwith 5 mL of trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na, Gibco Cat. #25300-070) for 1 min The trypsin is removed by aspiration and the cellsdislodged by tapping. Cell Culture medium (e.g. 30 mL for 1:30 split) isimmediately added and mixed well to inactivate trypsin. 1 mL of detachedcells is added to new culture flasks containing fresh Cell Culturemedium (e.g. into 25 mL per T-150 flask), and mixed gently. The cellsare incubated at 37° C. in 5% CO₂. The medium is changed at 3 to 4 daysinterval (or as appropriate). The cells grow to confluency(approx. >75%–95%) within 7–8 days. All steps are done under sterileconditions.

B. Membrane Preparation:

The cells are washed twice gently with Hank's Balanced Salt solution(e.g., use 10 mL per T-150 flask). The excess solution is removed andthe cells bathed for 15–30 min. in an enzyme-free Cell DissociationBuffer (e.g., use 8 mL Hank's Based, Gibco Cat. # 13150-016 per T-1 50flask) until cells are loosened. The contents are transferred tocentrifuge tubes (50 mL size) kept in ice bath. All subsequent steps aredone at 4° C. The tubes are centrifuged at 300×g for 15 min (1380 rpm onSORVAL, Model RT6000D, using rotor for 50 mL tubes). The supernatant isdiscarded and the cells suspended in homogenizing buffer (10 mM Tris-HClcontaining 0.25 M sucrose and 1 mM EDTA, pH 7.4) ensuring that thevolume of the buffer is about ten times the volume of the cell pellet.The cells are pooled into a centrifuge tube (50 mL) and homogenized witha Polytron at setting 6 for 10 sec. The homogenate is transferred into aPotter-Elvjehm homogenizer and homogenized with 3 strokes. Thehomogenate is centrifuged at 1500×g for 10 min at 4° C. (3100 rpm usingSORVAL, model RT6000D, using a rotor for 50 mL tubes). The pellet isdiscarded. The supernatant is centrifuged at 100,000×g for 60 min. at 4°C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpm with rotor type70 Ti for 50 mL tubes; 38,000 rpm with rotor type 8OTi for 15 mL tubes;or 35,800 rpm with rotor type 45Ti). The supernantant is discarded andthe pellet suspended in 3 to 4 mL of Tris buffer (50 mM TRIS-HCl, pH7.4). The protein content is estimated by the Bradford or Lowry method.The volume of the membrane suspension is adjusted with the membranebuffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) to give 3.0mg/mL (or as appropriate) of protein. The membranes are aliquoted andstored at −70° C.

C. Radioligand Binding Assay:

In wells of a 96-well format microtiter plate, is added 90, 110 or 130μL (to make up a final volume of 200 μL) of assay buffer containing 50mM of Tris-HCl (pH 7.4), BSA (heat inactivated, protease-free), 5 mM of0.1% MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin, 2 mg %1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF. Theinhibitors are added on the day of the experiment. The components aremixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4. To each well is added 20 μL of unlabeledoxytocin (to give a final concentration of 0.1 to 10 nM for standardcurve and 1000 nM for non specific binding) or test compounds in 50%DMSO (e.g. for final concentrations of 0.1 to 1000 nM or as appropriate)or 50% DMSO as vehicle control. For oxytocin and other peptide ligands,20 μL of 50% DMSO is added and the assay buffer volume is adjustedaccordingly. To each well is added 50 μL of frozen membrane suspensionthawed immediately prior to use and diluted in assay buffer to therequired concentration (equivalent to 25 to 50 μg of protein/well asneeded). 20 μL of 8 nM [³H]oxytocin in the assay buffer, prepared justbefore use is added and incubated at room temperature for 60 min.shaking the plate on a mechanical shaker for the first 15 min. Theincubation is stopped by rapid filtration of the plate contents followedby washing with ice-cold buffer (50 mM Tris-HCl, pH 7.4) using a cellharvester (Tomtek and Printed filtermat-B filter paper). The filterpaper is thoroughly dried (7–12 min. in a microwave oven) andimpregnated with MeltiLex B/H melt-on scintillation wax sheets and theradioactivity counted in a betaplate scintillation counter.

Binding data is either reported as percent inhibition at a certainconcentration or if an IC₅₀ was calculated, as a nanomolarconcentration. The results of these tests on representative compounds ofthis invention are shown in Table I.

TABLE 1 Binding to membranes of Chinese Hamster Ovary (CHO) cell linestably transfected with human vasopressin V_(1a) receptor subtype, humanvasopressin V₂ receptor subtype and human oxytocin receptor V₂ OT V_(1a)% inhibition % inhibition @ 100 % inhibition @ 100 (IC₅₀, nM)*n @Example nM (IC₅₀, nM)* nM (IC₅₀, nM)* 100 nM 1 (11.2)  9 18 2 (16.8)   (3180)   (1418) 3 (45) (>3000) (>3000) 4  (2.44) (791.78) (463.73) 5(10.2)  (>3000)    (433) 6  (7.51) (927.96) (308.77) 7  (3.34)    (803)   (407) 8  (4.65)    (801)    (237) 24 50 7 26 25 50 21 33 26 47 17 2327 22 20 16 28 50 28 20 29 42 0 12 30 25 −7 14 31 18 6 31 32 47 13 21 3342 23 21 34 5 5 5 35 27 4 14 36 46 −3 24 37 60 12 7 38 26 0 21 39 35 1011 40 17 15 11 41 41 20 16 42 33 −11 8 43 18 −6 7 44 22 11 31 45 37 5 1946 31 7 8 47 1 −1 6 48 15 0 9 49 58 1 26 50 67 26 17 51 31 2 16 52 51 168 53 6 11 13 54 55 30 18 55 50 −7 5 56 31 −11 11 57 32 2 33 58 37 9 2259 40 12 4 60 11 4 15 61 26 6 14 62 (10.68)    (177)   (1491) 63  (5.08)(273.45) (714.49) 64 91 21 13 65 95 25 16 66 92 58 24 67 91 40 24 68 9381 13 69 94 72 15 70 77 8 10 71 81 20 24 72 89 54 11 73 32 6 16 74 91 631 75 62 −1 9 76 62 11 21 77 21 5 10 78 59 6 8 79 49 18 10 80 50 6 8 8150 −6 5 82 27 −1 8 83 30 9 22 84 46 3 14 85 32 −5 5 86 21 1 11 87 52 1 488 44 8 13 89 67 29 15 90 44 14 11 91 44 11 10 92 30 21 0 93 69 50 27 9437 0 5 95 7 1 −1 96 28 7 22 97 36 4 16 98 39 24 10 99 13 −7 12 100 24 100 101  (2.23)    (355)    (270) 102  (4.14)    (275)    (534) 103 (6.25) (448.88) (318.40) 104 99 32 23 205 −9 0 6 106 98 68 −10 107 9212 30 108 83 4 24 109 70 7 0 110 94 49 32 111 36 4 23 112  (3.87)  (1597)   (1126) 113 (10.77)    (365)    (545) 114 94 56 18 115 66 22 8116 101 77 63 117 13 1 4 118 83 62 −10 119 83 9 17 120 67 6 16 121 57 17−4 122 61 9 −10 123 95 71 30 124 24 11 18 125 94 17 −10 126 93 38 5 127102 66 15 128 88 31 10 129 98 54 28 130 0 5 12 131 99 83 −5 132 99 26 25133 87 19 15 134 88 30 1 135 96 68 35 136 44 7 19 137 95 −1 11 138 97 842 139 96 21 34 140 95 −3 29 141 96 9 40 142 93 −5 16 144 57 11 2 145 22−1 2 146 38 11 15 147 64 15 21 *Binding in Chinese Hamster Ovary cellmembranes expressing human vasopressin V_(1a) and V₂ subtype receptorsand human oxytocin receptorsThe following examples are presented to illustrate rather than limit thescope of this invention.

EXAMPLE 1[10-(2-Methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-(4-pyridin-4-yl)-piperazin-1-yl)-methanone

Step A. 4-Bromo-3-methylbenzoic acid methyl ester

To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5 mmol) inmethanol (125 mL) was added concentrated sulfuric acid (1 mL). Thereaction was heated at reflux overnight with a homogeneous solutionobtained after several minutes of heating. After cooling, the methanolwas removed in vacuo and the residue was dissolved in dichloromethaneand washed with saturated aqueous sodium bicarbonate. The organic phasewas dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give 10.2 g of title compound as a brown solid, m.p. 41–43° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.39 (s, 3H), 3.85 (s, 3H), 7.64–7.72 (m,2H), 7.88–7.89 (m, 1H).

MS [EI, m/z]: 228 [M]⁺.

Anal. Calcd. for C₉H₉BrO₂: C, 47.19, H, 3.90. Found: C, 47.22, H, 3.80.

Step B. (2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylicacid methyl ester

A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A (2.0 g,8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7 mmol) andsodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25mL: 25 mL) was purged with nitrogen for 1 hour. After addition of thetetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol)the reaction was heated at 100° C. overnight. The cooled reactionmixture was filtered through Celite and the cake washed with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification by flash chromatography with a solvent gradient of 25% to50% dichloromethane in hexane provided 2.0 g of the title compound as acolorless oil.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.03 (s, 3H), 3.88 (s, 3H), 7.26 (d, 1H),7.34 (d, 1H), 7.66 (t, 1H), 7.75 (t, 1H), 7.81–7.83 (m, 1H), 7.86–7.88(m, 1H), 7.90–7.91 (m, 1H)

MS [ESI, m/z]: 312 [M+NH₄]⁺.

Anal. Calcd. for C₁₆H₁₃F₃O₂: C, 65.31, H, 4.45. Found: C, 64.92, H,4.54.

Step C. (2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylicacid

To a solution of(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylic acidmethyl ester of Step B (1.9 g, 6.5 mmol) in tetrahydrofuran (30 mL) wasadded 1 N sodium hydroxide (13 mL, 13 mmol). The reaction mixture washeated at reflux overnight, then cooled and acidified with 2 Nhydrochloric acid. The aqueous layer was extracted with ethyl acetateand the combined extracts were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give 1.65 g of the title compoundas a white solid, m.p. 171–174° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.02 (s, 3H), 7.23 (d, 1H), 7.34 (d, 1H),7.65 (t, 1H), 7.75 (t, 1H), 7.79–7.81 (m, 1H), 7.86–7.89 (m, 2H), 13.00(br, 1H).

MS [(−)ESI, m/z]: 279 [M−H]⁻.

Anal. Calcd. for C₁₅H₁₁F₃O₂: C, 64.29, H, 3.96. Found: C, 64.26, H,3.80.

Step D.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone

A suspension of(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-carboxylic acid ofStep C (0.50 g, 1.78 mmol) in thionyl chloride (3 mL) was heated atreflux for 90 minutes. After cooling, the thionyl chloride was removedin vacuo and the residue dissolved in toluene. The solution wasconcentrated in vacuo to yield the crude acid chloride as a brown oil.The acid chloride was dissolved in dichloromethane (5 mL) and slowlyadded to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.49 g, 2.66 mmol)and N,N-diisopropylethyl amine (0.68 mL, 3.90 mmol) in dichloromethane(15 mL). After stirring for 2 hours, the reaction was quenched withwater. The organic layer was sequentially washed with 1 N hydrochloricacid, 1 N sodium hydroxide and brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a yellow foam.Purification by flash chromatography using a solvent gradient of 15 to25% ethyl acetate in hexane gave a white foam which was crystallized bysonication from ethanol/hexane to provide the title compound (0.55 g) asa white solid, m.p. 127–130° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.86 (s, 3H), 4.80–5.40 (br, 4H), 5.93–5.98(m, 2H), 6.85 (t, 1H), 6.91–6.96 (m, 2H), 7.03–7.05 (m, 1H), 7.10–7.14(m, 1H), 7.19–7.24 (m, 2H), 7.29 (s, 1H), 7.47–7.49 (m, 1H), 7.61 (t,1H), 7.70 (t, 1H), 7.81 (d, 1H).

MS [EI, m/z]: 446 [M]⁺.

Anal. Calcd. for C₂₇H₂₁F₃N₂O: C, 72.64, H, 4.74, N, 6.27. Found: C,72.48, H, 4.57, N, 6.16.

Step E.2,2,2-Trichloro-1-(10-{[2-methyl-2′-trifluoromethyl-[1–1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanone

To a solution of(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanoneof Step D (1.87 g, 4.19 mmol) in dichloromethane (20 mL) was addedN,N-diisopropylethyl amine (1.46 mL, 8.38 mmol) followed by the slowaddition of trichloroacetyl chloride (1.45 mL, 13.0 mmol). The reactionmixture was stirred overnight at room temperature, and then quenchedwith water. The organic phase was washed with 0.1 N hydrochloric acidfollowed by water, then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a green oil. Purification by flashchromatography using a solvent system of 20% ethyl acetate in hexaneprovided 2.2 g of title product as a pale, yellow foam.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 5.25 (br, 2H), 5.97 (br, 2H),6.37 (d, 1H), 6.89–6.92 (m, 2H), 7.02–7.04 (m, 1H), 7.06–7.10 (m, 1H),7.15–7.22 (m, 2H), 7.28 (s, 1H), 7.41–7.46 (m, 2H), 7.58 (t, 1H), 7.67(t, 1H), 7.79 (d, 1H).

MS [(+)APCI, m/z]: 591 [M+H]⁺.

Anal. Calcd. for C₂₉H₂₀Cl₃F₃N₂O₂+0.20 C₄H₈O₂+0.80 H₂O: C, 57.37, H,3.75, N, 4.49. Found: C, 57.06, H, 3.39, N, 4.50.

Step F.10-(2-Methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

To a solution of2,2,2-trichloro-1-(10-{[2-methyl-2′-(trifluoromethyl)[1-1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanoneof Step E (2.3 g, 3.9 mmol) in acetone (20 mL) was added 2.5 N sodiumhydroxide (3.1 mL, 7.8 mmol). After stirring overnight, the reactionmixture was acidified with 2 N hydrochloric acid (4.3 mL, 8.6 mmol) andthen concentrated in vacuo. The residue was partitioned between ethylacetate and water. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a brown solid.Trituration with diethyl ether/hexane provided the title compound (1.32g) as a white solid, m.p. 233–235° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 5.17 (br, 2H), 5.94 (br, 2H),6.10–6.11 (m, 1H), 6.76 (d, 1H), 6.85–6.91 (m, 2H), 7.00–7.06 (m, 2H),7.12–7.16 (m, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.32–7.34 (m, 1H), 7.59(t, 1H), 7.68 (t, 1H), 7.79 (d, 1H), 12.33 (br, 1H).

MS [ESI, m/z]: 491 [M+H]⁺.

Anal. Calcd. for C₂₈H₂₁F₃N₂O₃: C, 68.57, H, 4.32, N, 5.71. Found: C,68.39; H, 4.25, N, 5.64.

Step G.[10-(2-Methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-(4-pyridin-4-yl-piperazin-1-yl)-methanone

To a solution of10-(2-methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step F (0.50 g, 1.02 mmol), 1-(4-pyridinyl)-piperazine (0.20 g,1.23 mmol) and 1-hydroxybenzotriazole monohydrate (0.15 g, 1.11 mmol) inN,N-dimethylformamide (4 mL) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.22 g,1.15 mmol) followed by N,N-diisopropylethyl amine (0.27 mL, 1.55 mmol).The reaction mixture was stirred overnight, diluted with ethyl acetateand washed with water and saturated aqueous sodium bicarbonate. Theorganic phase was then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a yellow oil. Purification by flashchromatography using a solvent system of 10% methanol in chloroformprovided 0.39 g of the title product which was dissolved indichloromethane and concentrated in vacuo to a white foam.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 3.40–3.43 (m, 4H), 3.74–3.76(m, 4H), 5.15 (broad s, 2H), 5.44 (s, 2H), 6.09 (d, 1H), 6.32 (d, 1H),6.82–6.90 (m, 4H), 6.99–7.06 (m, 2H), 7.13 (t, 1H), 7.22 (d, 1H), 7.26(s, 1H), 7.40–7.42 (m, 1H), 7.58 (t, 1H), 7.67 (t, 1H), 7.79 (d, 1H),8.17–8.19 (m, 2H).

MS [(+)APCI, m/z]: 636 [M+H]⁺.

Anal. Calcd. for C₃₇H₃₂F₃N₅O₂+0.14 CH₂Cl₂+0.04 C₃H₇NO: C, 68.80, H,5.05, N, 10.85. Found: C, 66.63, H, 4.97, N, 10.41.

EXAMPLE 210-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-3-({4-[(1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

Step A. 3-Chloromethyl-pyridine-1-oxide

To a solution of 3-hydroxymethyl-pyridine N-oxide (1.0 g, 8.0 mmol) indichloromethane (40 mL) was added thionyl chloride (10 mL, 137 mmol).After stirring for 2 hours, the reaction mixture was concentrated invacuo. The residue was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate. The aqueous layer was repeatedly extractedwith dichloromethane. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give0.60 g of the title product as a white solid, m.p. 133–137° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 4.74 (s, 2H), 7.40–7.45 (m, 2H), 8.17–8.20(m, 1H), 8.35 (s, 1H).

MS [(+)APCI, m/z]: 144 [M+H]⁺.

Anal. Calcd. for C₆H₆ClNO: C, 50.19, H, 4.21, N, 9.76. Found: C, 49.56,H, 4.21, N, 9.58.

Step B.4-[[10,11-Dihydro-10-[[2-methyl-2-trifluoromethyl-[1,1-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazinecarboxylicacid, tert-butyl ester

10-(2-Methyl-2-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 1, Step F (1.0 g, 2.04 mmol),1-(tert-butoxycarbonyl)piperazine (0.46 g, 2.47 mmol) and1-hydroxybenzotriazole monohydrate (0.30 g, 2.22 mmol) were dissolved inN,N-dimethylformamide (8 mL). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.43 g, 2.24 mmol) was then added followedby N,N-diisopropylethyl amine (0.55 mL, 3.09 mmol). The reaction mixturewas stirred overnight, diluted with ethyl acetate and washed with waterand saturated aqueous sodium bicarbonate. The organic phase was thendried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give a brown oil. Purification by flash chromatography using asolvent gradient from 30% to 50% of ethyl acetate in hexane provided 1.1g of the desired title compound as a white foam, m.p. 104–121° C. Thismaterial was redissolved in dichloromethane and concentrated in vacuo toa white foam.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.41 (s, 9H), 1.83 (s, 3H), 3.38 (br, 4H),3.59–3.61 (m, 4H), 5.15 (br, 2H), 5.41 (s, 2H), 6.07 (d, 1H), 6.28 (d,1H), 6.85–6.90 (m, 2H), 6.99–7.06 (m, 2H), 7.12–7.16 (m, 1H), 7.21 (d,1H), 7.25 (s, 1H), 7.40–7.42 (m, 1H), 7.58 (t, 1H), 7.67 (t, 1H), 7.79(d, 1H).

MS [(+)APCI, m/z]: 659 [M+H]⁺.

Anal. Calcd. for C₃₇H₃₇F₃N₄O₄+0.09 CH₂Cl₂+0.18 C₄H₈O₂ C, 66.56, H, 5.71,N, 8.21. Found: C, 66.27, H, 5.40, N, 8.00.

Step C.10,11-Dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinehydrochloride salt

The4-[[10,11-dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazinecarboxylicacid, tert-butyl ester of Step B (0.85 g, 1.29 mmol) was then added inone portion to stirred ethyl acetate (10 mL) saturated with hydrogenchloride gas at 0° C. The reaction mixture was stirred for 90 minutesunder anhydrous conditions. A precipitate formed after several minutes.The reaction was then warmed to room temperature and diluted withdiethyl ether. The precipitated product was collected by filtration anddried under high vacuum to provide 0.65 g of the desired title compoundhydrochloride salt as an off-white foam.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 3.16 (br, 4H), 3.83–3.85 (m,4H), 5.15 (br, 2H), 5.43 (s, 2H), 6.09 (d, 1H), 6.38 (d, 1H), 6.87–6.91(m, 2H), 6.99–7.01 (m, 1H), 7.06 (t, 1H), 7.13–7.17 (m, 1H), 7.21 (d,1H), 7.26 (s, 1H), 7.44–7.46 (m, 1H), 7.59 (t, 1H), 7.68 (t, 1H), 7.79(d, 1H), 9.28 (br, 2H).

MS [(+)APCI, m/z]: 559 [M+H]⁺.

Anal. Calcd. for C₃₂H₂₉F₃N₄O₂+1.0 HCl+1.00 H₂O+0.06 C₄H₁₀O: C, 62.70, H,5.32, N, 9.07. Found: C, 62.42, H, 5.22, N, 8.94.

Step D.10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-3-({4-[(1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of the10,11-dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinehydrochloride salt of Step C (0.50 g, 0.84 mmol),3-chloromethyl-pyridine-1-oxide of Step A (0.11 g, 0.77 mmol) andN,N-diisopropylethyl amine (0.30 mL, 1.70 mmol) in N,N-dimethylformamide(10 mL) was heated at 50° C. The reaction was then cooled, quenched withsaturated aqueous sodium bicarbonate and extracted with chloroform. Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a yellow oil. Purification byflash chromatography using a solvent system of 5% methanol indichloromethane provided 0.47 g of the title compound as a yellow foam.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 2.42 (br, 4H), 3.52 (m, 2H),3.64 (br, 4H), 5.15 (br, 2H), 5.40 (s, 2H), 6.06 (d, 1H), 6.24 (d, 1H),6.84–6.90 (m, 2H), 6.99–7.06 (m, 2H), 7.15 (t, 1H), 7.21 (d, 1H), 7.25(s, 1H), 7.29 (d, 1H), 7.35–7.42 (m, 2H), 7.58 (t, 1H), 7.68 (t, 1H),7.79 (d, 1H), 8.11 (d, 1H), 8.17 (s, 1H).

MS [(+)APCI, m/z]: 666 [M+H]⁺.

Anal. Calcd. for C₃₈H₃₄F₃N₅O₃+1.00 H₂O+0.11 CH₂Cl₂: C, 66.04, H, 5.27,N, 10. Found: C, 65.88, H, 5.03, N, 10.03.

EXAMPLE 33-({4-[(2-Methyl-1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

Step A. 3-Hydroxymethyl-2-methyl-pyridine

Prepared according to a slightly modified procedure of I. M. Bell etal., J. Med. Chem. 41, 2146–2163 (1998). To a stirred solution of ethyl2-methylnicotinate (2.0 g, 12.1 mmol) in tetrahydrofuran (40 mL) cooledto 0° C. was slowly added a 1 M solution of diisobutyl aluminum hydridein tetrahydrofuran (30 mL, 30 mmol). After 5 minutes, the reaction wasquenched with saturated aqueous sodium bicarbonate and saturated aqueoussodium potassium tartrate. The aqueous phase was repeatedly extractedwith chloroform. The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give 2.5 g of thecrude title compound as a yellow oil. The crude material was used assuch in the next step.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.40 (s, 3H), 4.49 (d, 2H), 5.23 (t, 1H),7.16–7.19 (m, 1H), 7.67–7.69 (m, 1H), 8.28–8.31 (m, 1H).

MS [(+)APCI, m/z]: 124 [M+H]⁺.

Step B. 3-Chloromethyl-2-methyl-pyridine

Prepared essentially according to the procedure of I. M. Bell et al., J.Med. Chem. 41, 2146–2163 (1998). To a stirred solution of the3-hydroxymethyl-2-methyl-pyridine of Step A (2.5 g, 20.3 mmol) indichloromethane (100 mL) was added thionyl chloride (15 mL, 206 mmol).After stirring for 2 hours, the reaction mixture was concentrated invacuo. The residue was partitioned between dichloromethane and saturatedaqueous sodium bicarbonate. The aqueous layer was repeatedly extractedwith dichloromethane. The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give1.35 g of the title compound as an orange oil which was immediately usedin the next step.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.54 (s, 3H), 4.82 (s, 2H), 7.21–7.24 (m,1H), 7.75–7.78 (m, 1H), 8.39–8.41 (m, 1H).

MS [(+)APCI, m/z]: 142 [M+H]⁺.

Step C. 3-Chloromethyl-2-methyl-pyridine 1-oxide

Prepared essentially according to the procedure of I. M. Bell et al., J.Med. Chem. 41, 2146–2163 (1998). To a stirred solution of the crude3-hydroxymethyl-2-methyl-pyridine of Step B (1.35 g, 9.53 mmol) inchloroform (50 mL) was added 90% m-chloroperbenzoic acid (2.0 g, 10.4mmol). After stirring overnight at room temperature, an additionalquantity of 90% m-chloroperbenzoic acid (1.0 g, 5.2 mmol) was added. Thereaction mixture was stirred for an additional 3 hours and then quenchedwith saturated aqueous sodium bicarbonate. The organic layer was washedwith water, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a yellow solid. Purification by flashchromatography using a solvent system of 3% methanol in chloroformprovided 0.85 g of the title compound as a brown-orange amorphous solid.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.41 (s, 3H), 4.84 (s, 2H), 7.26–7.29 (m,1H), 7.38–7.40 (m, 1H), 8.25–8.27 (m, 1H).

MS [(+)APCI, m/z]: 158 [M+H]⁺.

Anal. Calcd. for C₇H₈ClNO: C, 53.35, H, 5.12, N, 8.89. Found: C, 52.69,H, 4.64, N, 8.06.

Step D.3-({4-[(2-Methyl-1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A stirred mixture of the10,11-dihydro-10-[[2-methyl-2-(trifluoromethyl)[1,1-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinehydrochloride salt of Example 2, Step C (0.50 g, 0.84 mmol),3-chloromethyl-2-methyl-pyridine 1-oxide of Step B (0.13 g, 0.82 mmol)and N,N-diisopropylethyl amine (0.30 mL, 1.70 mmol) inN,N-dimethylformamide (10 mL) was heated at 50° C. overnight. Thereaction mixture was then cooled, quenched with saturated aqueous sodiumbicarbonate and extracted with chloroform. The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give a yellow oil. Purification by flash chromatography using asolvent system of 5% methanol in dichloromethane provided 0.41 g of thetitle product as a white foam.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 2.40 (s, 3H), 2.43 (br, 4H),3.53 (s, 2H), 3.62 (br, 4H), 5.15 (br, 2H), 5.41 (s, 2H), 6.06 (d, 1H),6.23 (d, 1H), 6.85–6.90 (m, 2H), 6.99–7.06 (m, 2H), 7.13–7.17 (m, 1H),7.20–7.26 (m, 4H), 7.38–7.40 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79(d, 1H), 8.19–8.20 (m, 1H).

MS [ESI, m/z]: 680 [M+H]⁺.

Anal. Calcd. for C₃₉H₃₆F₃N₅O₃+0.50 H₂O+0.40 CH₂Cl₂: C, 65.48; H, 5.27,N, 9.69. Found: C, 65.08, H, 5.04, N, 9.62.

EXAMPLE 4N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[(1-oxidopyridin-3-yl)methyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. tert-Butyl methyl(pyridin-3-ylmethyl)carbamate

To a stirred solution of 3-(methylaminomethyl) pyridine (1.0 g, 8.2mmol) in dichloromethane (20 mL) was added di-tert-butyl dicarbonate(1.8 g, 8.2 mmol). After 10 minutes, the reaction was quenched withwater. The organic layer was washed with 5% aqueous sodium bicarbonate,dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give 1.8 g of crude product as a pale yellow oil, which was used assuch in the next step.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.10 (s, 9H), 2.77 (s, 3H), 4.38 (s, 2H),7.35–7.38 (m, 1H), 7.60–7.62 (d, 1H), 8.44–8.48 (m, 2H).

MS [ESI, m/z]: 223 [M+H]⁺.

Step B. tert-Butyl methyl[(1-oxidopyridin-3-yl)methyl]carbamate

To a stirred solution of tert-butyl methyl(pyridin-3-ylmethyl)carbamateof Step A (0.50 g, 2.25 mmol) in dichloromethane (15 mL) was added 90%m-chloroperbenzoic acid (1.3 g, 6.8 mmol). After stirring overnight, thereaction was quenched with saturated aqueous sodium bicarbonate. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give 0.38 g of product as a colorless oil.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.40 (br, 9H), 2.80 (s, 3H), 4.32 (s, 2H),7.16 (d, 1H), 7.39 (t, 1H), 8.07 (s, 1H), 8.12 (d, 1H).

MS [ESI, m/z]: 239 [M+H]⁺.

Step C. Methyl-(1-oxy-pyridin-3-ylmethyl)-amine dihydrochloride

Hydrogen chloride gas was bubbled for 15 minutes into a solution oftert-butyl methyl[(1-oxidopyridin-3-yl)methyl]carbamate of Step B (0.38g, 1.60 mmol) in ethyl acetate (10 mL) kept at 0° C. A drying tube wasattached, and the reaction warmed to room temperature while stirring for1 hour. The reaction was then concentrated in vacuo to give 0.31 g ofthe title product as an amorphous white solid, which is used as such inthe nest step.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.52 (t, 3H), 4.16 (t, 2H), 7.64–7.67 (m,1H), 7.86(d, 1H), 8.46–8.48 (m, 1H), 8.60 (br, 1H), 8.68 (s, 1H), 9.75(br, 2H).

MS [(+)APCI, m/z]: 139 [M+H]⁺.

Anal. Calcd. for C₇H₁₀N₂O+2 HCl: C, 39.83, H, 5.73, N, 13.27. Found:40.01, H, 5.77, N, 13.19.

Step D.N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[(1-oxidopyridin-3-yl)methyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

To a stirred solution of the10-(2-methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 1, Step F (0.50 g, 1.02 mmol),methyl-(1-oxy-pyridin-3-ylmethyl)-amine dihydrochloride of Step C (0.26g, 1.23 mmol) and 1-hydroxybenzotriazole (0.16 g, 1.18 mmol) inN,N-dimethylformamide (4 mL) was added1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.21 g,1.10 mmol) followed by N,N-diisopropylethyl amine (0.73 mL, 4.10 mmol).The reaction mixture was stirred overnight, diluted with ethyl acetateand washed with water and saturated aqueous sodium bicarbonate. Theorganic phase was then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a yellow foam. Purification by flashchromatography eluting with 2% methanol in chloroform provided 0.52 g ofthe title compound, which was redissolved in dichloromethane andconcentrated in vacuo to give a white foam.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 3.07 (s, 3H), 4.67 (s, 2H),5.15 (br, 2H), 5.49 (s, 2H), 6.08 (d, 1H), 6.40 (br, 1H), 6.86–6.91 (m,2H), 7.00–7.07 (m, 2H), 7.13–7.17 (m, 1H), 7.22 (d, 1H), 7.26–7.29 (m,2H), 7.39–7.45 (m, 2H), 7.59 (t, 1H), 7.68 (t, 1H), 7.80 (d, 1H),8.15–8.19 (m, 2H).

MS [ESI, m/z]: 611 [M+H]⁺.

Anal. Calcd. for C₃₅H₂₉F₃N₄O₃+0.14 CH₂Cl₂+0.14 CHCl₃: C, 66.29, H, 4.64,N, 8.76. Found: C, 64.26, H, 3.98, N, 8.39.

EXAMPLE 510-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. 4-Iodo-5-chloro-2-methoxy benzoic acid

A stirred solution of 4-amino-5-chloro-2-methoxy benzoic acid (12.25 g ,60.8 mmol) in water (136 mL) and concentrated sulfuric acid (34 mL) wascooled to 0° C. in a flask fitted with an overhead stirrer. A solutionof sodium nitrite (4.62 g , 66.9 mmol) in water (26 mL) was addeddropwise while keeping the internal temperature around 0° C. Potassiumiodide (11.11 g, 66.9 mmol) and iodine (4.24g, 33.5 mmol) were dissolvedin water (130 mL) and added dropwise to the stirred reaction mixture.After 2 hours the reaction was extracted with ethyl acetate. The organicextracts were then washed with 10% sodium thiosulfate and brine, thendried over magnesium sulfate, filtered and evaporated to dryness toyield 11.32 g of the title compound, m.p. 150–151° C. This material wasused without further purification.

¹H NMR (DMSO-d₆, 400 MHz): δ 13.03 (br, 1H), 7.70 (s, 1H), 7.63 (s, 1H),3.82 (s, 3H).

MS [(−)-APCI, m/z]: 311 [M−H]⁻

Anal. Calcd. for C₈H₆ClIO₃: C, 30.75, H, 1.94. Found: C, 31.28, H, 1.78.

Step B.2-Chloro-2′-trifluoromethyl-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid

To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid of StepA (3.12 g, 10 mmol) in N,N-dimethylformamide(100 mL) was added2-trifluoromethyl phenyl boronic acid (5.70 g, 30 mmol) and potassiumcarbonate (12.73 g, 92 mmol). This mixture was purged with nitrogen andthen treated with a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol). The reaction was heated to refluxovernight, cooled, acidified with 2N hydrochloric acid and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered, and evaporated to provide anearly quantitative amount of the title acid which was used in the nextstep without further purification.

Step C.10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A stirred solution of the2-chloro-2′-trifluoromethyl-5-methoxy-[1,1′-biphenyl]-4-carboxylic acidof Step B (3.46 g, 10.46 mmol) in tetrahydrofuran (20 mL) containing acatalytic amount of N,N-dimethylformamide was treated dropwise withthionyl chloride (1.36 g, 11.51 mmol). The reaction mixture was stirredfor 2 hours, and then added dropwise to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.92 g 10.46 mmol)in tetrahydrofuran (20 mL) containing triethylamine (2.32 g, 23 mmol).The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Trituration of the residue withacetone gave 3.14 g of the title compound. Recrystallization fromacetone/hexane provided white crystals, m.p. 208–210° C.;

¹H NMR (DMSO-d₆, 400 MHz) δ 3.46 (s, 3H), 5.16–5.20 (br, d, 3H), 5.89(t, 1H), 5.97 (s, 1H), 6.70 (s, 1H), 6.80 (t, 1H), 7.80–7.00 (m, 10H).

MS [(+) ESI, m/z]: 497 [M+H]⁺.

Anal. Calcd. for C₂₇H₂₀ClF₃N₂O₂+0.5 H₂O: C, 64.10, H, 4.18, N, 5.54.Found: C, 64.40, H, 3.97, N, 5.54.

Step D.10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

A solution of the10-{[6-chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step C (2.29 g, 4.6 mmol) in dichloromethane (30 mL) was treated withN,N-diisopropylethylamine (0.62 g, 4.84 mmol) and stirred for 10minutes. Trichloroacetylchloride (0.92 g, 5.07 mmol) was then addeddropwise. The reaction mixture was stirred overnight, diluted withdichloromethane, washed with 0.1N hydrochloric acid, saturated aqueoussodium bicarbonate, and brine. The organic phase was dried overanhydrous magnesium sulfate, filtered, and evaporated to yield the crudetrichloroketone intermediate which without further purification, wasdissolved in acetone and treated with an excess of 1N sodium hydroxideThe mixture was stirred overnight, and then diluted with isopropylacetate and acidified with 1 N hydrochloric acid. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andevaporated to dryness. The solid residue was triturated with methanol toprovide the title compound (1.23 g ) as a white solid, m.p. 220–222° C.(dec).

¹H NMR (DMSO-d₆, 400 MHz) δ 3.40 (s, 3H), 6.12 (d, 1H), 6.68 (s, 1H),6.72 (d, 1H), 6.94 (s, 2H), 7.07 (t, 1H), 7.25 (d, 2H), 7.62 (t, 2H),7.70 (t, 1H), 7.78 (d, 1H), 12.31 (br, 1H).

MS [(+)APCI, m/z]: 541 [M+H]⁺.

Anal. Calcd. for C₂₈H₂₀ClF₃N₂O₄+0.25 H₂O: C, 61.66, H, 3.79, N, 5.14.Found: C, 61.47, H, 3.64, N, 5.06.

Step E.10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

To a stirred solution of the10-{[6-chloro-3-methoxy-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step D (0.250 g, 0.46 mmol) in N,N-dimethylformamide (2 mL) wasadded 3-(methylaminomethyl)pyridine (0.068 g, 0.55 mmol),1-hydroxybenzotriazole (0.069 g, 0.51 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.087 g,0.51 mmol), and N,N-diisopropylethyl amine (0.090 g, 0.69 mmol). Afterstirring overnight, the reaction mixture was taken up in chloroform,washed with saturated aqueous sodium bicarbonate and brine, dried overmagnesium sulfate, filtered and evaporated to yield the title compound(0.153 g) as a solid which was recrystallized from ethyl acetate, m.p.124–126° C. The sample was shown to be 93% pure by analytical HPLC[Primesphere C-18 column (2.0×150 mm); mobile phase: 45/55acetonitrile/water containing 0.1% phosphoric acid].

¹H NMR (DMSO-d₆, 400 MHz) δ 3.02 (s, 3H), 3.41 (br, 3H), 4.74 (s, 2H),5.36 (br, 1H), 5.40 (br, 1H), 6.08 (d, 1H), 6.33 (s, 1H), 6.68 (s, 1H),6.95 (s, 2H), 7.09 (t, 1H), 7.25–7.90 (m, 8H), 8.51 (t, 2H).

MS [(+)APCI, m/z]: 645 [M+H]⁺.

Anal. Calcd. for C₃₅H₂₈ClF₃N₄O₃: C, 65.17, H, 4.38, N, 8.69. Found: C,63.84, H, 4.47, N, 9.00.

EXAMPLE 610-[(2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. 2-Chloro-2′-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid

To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid ofExample 5, Step A (3.38 g, 10.8 mmol) in N,N-dimethylformamide (80 mL)was added 2-chloro phenyl boronic acid (5.07 g, 32.4 mmol) and potassiumcarbonate (3.44 g, 32.4 mmol). This mixture was purged with nitrogen andthen treated with tetrakis(triphenylphosphine) palladium(0) (0.625 g,0.54 mmol). The reaction was heated to reflux overnight, cooled,acidified with 2 N hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate, filtered, and evaporated to provide 2.4 g of the title acidwhich was used in the next step without further purification.

Step B.10-{[2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A stirred solution of the2-chloro-2′-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step A(2.29 g, 7.71 mmol) in tetrahydrofuran (20 mL) containing a catalyticamount of N,N-dimethylformamide was treated dropwise with thionylchloride (1.00 g, 8.48 mmol). The reaction mixture was stirred for 2hours, and then added dropwise to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.42 g, 7.71 mmol)in tetrahydrofuran (20 mL) containing triethylamine (1.72 g, 16.96mmol). The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Trituration of the residue withethyl acetate provided 1.93 g of the title compound which wasrecrystallized from ethyl acetate/hexanes as white crystals, m.p.209–211° C.

¹H NMR (DMSO-d₆, 400 MHz) δ 3.55 (s, 3H), 5.16–5.20 (br, m, 3H), 5.89(t, 1H), 5.97 (s, 1H), 6.71 (s, 1H), 6.80 (s, 1H), 7.04–7.60 (m, 10H).

MS [(+)APCI, m/z]: 463 [M+H]⁺.

Anal. Calcd. for C₂₆H₂₀Cl₂N₂O₂+0.25 C₄H₈O₂: C, 66.81, H, 4.57, N, 5.77.Found: C, 66.76, H, 4.24, N, 5.93.

Step C.10-[(2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid.

A solution of the10-[(2′,6-dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step B (1.36 g, 2.94 mmol) in dichloromethane (25 mL) was treatedwith N,N-diisopropylethyl amine (0.398 g, 3.08 mmol) and stirred for 10minutes. Trichloroacetylchloride (0.587 g, 3.23 mmol) was then addeddropwise. The reaction mixture was stirred overnight, diluted withdichloromethane, washed with 0.1 N hydrochloric acid, saturated aqueoussodium bicarbonate, and brine. The organic phase was dried overanhydrous magnesium sulfate, filtered, and evaporated to yield the crudetrichloroketone intermediate which without further purification, wasdissolved in acetone and treated with an excess of 1 N sodium hydroxide.The mixture was stirred overnight, and then diluted with isopropylacetate and acidified with 1 N hydrochloric acid. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andevaporated to dryness. The solid residue was triturated with methanol toprovide the title compound (1.02 g) as a white powder which was used assuch in the next step.

Step D.10-[(2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

To a stirred solution of the10-[(2′,6-dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepinecarboxylic acid of Step C (0.250 g, 0.49 mmol) in N,N-dimethylformamide(2 mL) was added 3-(methylaminomethyl) pyridine (0,073 g, 0.59 mmol),1-hydroxybenzotriazole (0.074 g, 0.54 mmol),1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.093 g,0.54 mmol), and N,N-diisopropylethyl amine (0.096 g, 0.74 mmol). Afterstirring overnight, the reaction mixture was taken up in chloroform,washed with saturated aqueous sodium bicarbonate and brine, dried overmagnesium sulfate, filtered and evaporated to dryness. Trituration ofthe residue with ethyl acetate provided the title compound (0.225 g) asa white solid, m.p. 196–198° C., found to be 93.88% pure by analyticalHPLC [Primesphere C-18 column (2.0×150 mm); mobile phase: 45/55acetonitrile/water containing 0.1% phosphoric acid].

¹H NMR (DMSO-d₆, 400 MHz) δ 3.02 (s, 3H), 3.46 (br, s, 3H), 4.74 (s,2H), 5.38 (s, 2H), 6.08 (d, 1H), 6.33 (s, 1H), 6.69 (s, 1H), 6.98–7.72(m, 12H), 8.49–8.53 (m, 2H).

MS [(+)APCI, m/z]: 611 [M+H]⁺.

Anal. Calcd. for C₃₄H₂₈Cl₂N₄O₃: C, 66.78, H, 4.62, N, 9.16. Found: C,64.98, H, 4.63, N, 9.45.

EXAMPLE 710-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. Trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenyl ester

To a solution of vanillin (6.08 g, 40.0 mmol) and triethylamine (6.70mL, 48.0 mmol) in dichloromethane (300 mL) was added dropwise a solutionof trifluoromethanesulfonic anhydride (12.4 g, 44.0 mmol) indichloromethane (100 mL) at 0° C. After stirring for 2 hours, thesolution was concentrated, and the residue washed with water andextracted twice with ethyl acetate. Upon drying and concentrating, theresidual dark oil was subjected to flash chromatography on silica geleluting with 20% ethyl acetate in hexane providing the title product(8.91 g) as a light yellow oil, which was used in the next step withoutfurther purification.

Step B. 2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde

A stirred solution of trifluoromethanesulfonic acid4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol),2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassiumphosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) wasdegassed with nitrogen, whereupon a catalytic amount (0.285 g) of[1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added.The solution was heated to 120° C. for 5 hours, poured into water andextracted with ethyl acetate. The combined extracts were washed withwater, dried over anhydrous magnesium sulfate and filtered through aplug of silica gel. Removal of the solvent provided the crude titlecompound (4.54 g) as an oil, which was used as such in the next step.

¹H NMR (200 MHz, CDCl₃): δ 10.03 (s, 1H), 8.14 (d, 1H), 7.31–7.56 (m,6H), 3.91 (s, 3H).

Step C. 2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid

The 2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde ofStep B (0.95 g, 3.41 mmol) and sulfamic acid (0.43 g, 4.43 mmol) weredissolved in a mixture of tetrahydrofuran and water (1:1, v/v, 30 mL).Sodium chlorite (0.31 g, 4.43 mmol) was added under stirring, and thesolution turned yellow. After 30 minutes, additional sodium chlorite(0.1 g) and sulfamic acid were added, and the solution stirred anadditional hour. The solution was then concentrated, and the residuepartitioned between ethyl acetate and water. The ethyl acetate layer wasdried and concentrated to yield an oil, which solidified upontrituration with hexane to provide the title compound (0.84 g) as ayellow solid, which was used in the next step.

Step D. (10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone

The 2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid ofStep C (1.6 g, 5.40 mmol) was added to a flask containing toluene (30mL), thionyl chloride (1.4 mL) and one drop of N,N-dimethylformamide.The solution was stirred at 70° C. for 1 hour and then concentrated invacuo. The residue was diluted with dichloromethane (40 mL) and to thissolution was added 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine(0.94 g, 5.16 mmol). After the solution became homogeneous,N,N-diisopropylethyl amine (1.07 mL, 6.19 mmol) was added in one portionat 0° C. After 30 minutes the solution was concentrated, and the residuepartitioned between water and ethyl acetate. The ethyl acetate was driedand concentrated to give a crude oil, which was chromatographed onsilica gel eluting with 30% ethyl acetate in hexane to yield 1.2 g ofproduct. The solid was recrystallized from ethyl acetate/hexane toprovide the desired title product (0.87 g) as colorless crystals, m.p.146–148° C.

¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (d, 1H), 7.62 (t, 1H ), 7.53 (t, 1H),7.46 (d, 1H), 7.19 (m, 2H), 7.11 (t, 1H), 6.92–7.01 (m, 4H), 6.83 (s,1H), 5.95 (br, 1H), 5.91 (s, 1H), 5.31 (br, 4H), 3.45 (s, 3H).

MS [(+)ESI, m/z]: 463 [M+H]⁺.

Anal. Calcd. for C₂₇H₂₁F₃N₂O₂: C, 70.12, H, 4.58, N, 6.06. Found: C,70.53; 4 H, 4.72, N, 5.89.

Step E.10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

To a stirred solution of the(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanoneof Step D (2.34 g, 5.0 mmol) and N,N-diisopropylethyl amine (1.04 mL,6.0 mmol) in dichloromethane (100 mL) was added dropwise a solution oftrichloroacetyl chloride (1.09 g, 6.0 mmol) in dichloromethane (20 mL)kept at 0° C. After the addition was complete, the solution was stirredovernight at room temperature, then washed with 10% aqueous potassiumcarbonate. The organic phase was dried and concentrated to yield a blackresidue. The residue was purified by filtration through a plug of silicagel, eluting with 20% ethyl acetate in hexane. The resulting tan coloredproduct was dissolved in acetone and 1 N NaOH (2:1, v/v) and the mixturewas stirred for 30 minutes. The solution was then concentrated andextracted with ethyl acetate. The combined organic phases were dried andconcentrated to yield a yellow oil. The oil was triturated with hexane,and the resulting solid was removed by filtration to yield the titlecompound (1.86 g) as an off white solid, which was used without furtherpurification.

Step F.10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

To a stirred solution of the10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step E (0.17 g, 0.37 mmol) in N,N-dimethylformamide (15 mL), wasadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.092 g, 0.48 mmol) and 1-hydroxybenzotriazole monohydrate (0.065 g,0.48 mmol). After the solution became homogeneous 3-(methylaminomethyl)pyridine (0.045 g, 0.37 mmol) was added, and the solution was stirred atroom temperature overnight. The solution was then poured into water andextracted with ethyl acetate. The combined ethyl acetate layers werewashed with water, dried and concentrated to dryness. The residue wassubjected to silica chromatography eluting with 10% methanol inchloroform. The pure fractions were concentrated and the residueazeotroped and triturated several times with hexane to provide the titleproduct (0.150 g) as an amorphous white solid, 150–153° C. (dec.)

¹H NMR (400 MHz, DMSO-d₆): δ 3.14 (s, 3H), 3.46 (s, 3H), 4.82(s, 2H),5.52 (br, 2H), 6.06 (s, 1H), 6.43 (s, 1H), 6.85–6.97 (m, 4H), 7.04 (t,1H), 7.18 (t, 1H), 7.21 (d, 1H), 7.42 (d, 1H), 7.56 (t, 1H), 7.62 (t,1H), 7.74 (d, 1H), 7.86 (t, 1H), 8.29(m, 1H), 8.89 (m, 2H).

MS [EI, m/z]: 610 [M]⁺.

Anal. Calcd. for C₃₅H₂₉F₃N₄O₃: C, 64.96, H, 4.67, N, 8.66. Found: C,63.28, H, 4.85, N, 8.22.

EXAMPLE 810-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(1-oxo-pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

The title compound [white solid, 0.112 g, m.p. 165–170° C. (dec.)] wasprepared from10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo.[2,1-c][1,4].benzodiazepine-3-carboxylicacid of Example 7, Step E (0.225 g, 0.48 mmol) andmethyl-(1-oxy-pyridin-3-ylmethyl)-amine dihydrochloride of Example 4,Step C (0.140 g, 0.70 mmol) in the manner of Example 4, Step D.

¹H NMR (400 MHz, DMSO-d₆): δ 3.14 (s, 3H), 3.46(s, 3H), 4.62(s, 2H),5.52 (br, 2H), 6.06 (s, 1H), 6.41 (s, 1H), 6.85–6.973 (m, 4H), 7.04 (t,1H), 7.18 (t, 1H), 7.20(d, 1H), 7.23 (d, 1H), 7.42 (m, 2H), 7.56 (t,1H), 7.62 (t, 1H ), 7.74 (d, 1H), 8.18(m, 2H).

MS [EI, m/z]: 626 [M]⁺

Anal. Calcd. for C₃₅H₂₉F₃N₄O₄: C, 67.09, H, 4.66, N, 8.94. Found: C,65.28, H, 4.49, N, 8.00.

EXAMPLE 910-[4-(Naphthalen-1-yl)-benzoyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. 4-Naphthalen-1-yl-benzoic acid methyl ester

Methyl 4-bromobenzoate (0.96 g, 4.46 mmol) was added to a mixture of1-naphthaleneboronic acid (0.73 g, 4.25 mmol) and sodium carbonate(0.075 g, 7.08 mmol) in toluene (30 mL), ethanol (6 mL) and water (12mL). The resultant solution was purged with nitrogen for 10 minutesbefore tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.09 mmol) wasadded. The reaction mixture was heated to reflux for 65 hours. Thesolution was cooled to ambient temperature, then filtered through a padof Celite, which was subsequently rinsed with ethyl acetate. Thecombined filtrate was diluted to 100 mL with water/ethyl acetate (1:1).The aqueous layer was extracted with ethyl acetate, and the combinedextracts were dried over anhydrous magnesium sulfate, filtered, andevaporated to dryness to yield the title compound as a gold oil (1.09g). This material was used without further purification in the nextstep.

¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d, 2H), 8.02 (t, 2H), 7.75 (d, 1H),7.57 (m, 6H), 3.92 (s, 3H).

Step B. 4-Naphthalen-1-yl-benzoic acid

To a stirred solution of the 4-naphthalen-1-yl-benzoic acid methyl esterof Step A (1.09 g, 4.15 mmol), in methanol (18 mL) and water (6 mL),cooled to 5° C., was added lithium hydroxide monohydrate (0.42 g, 10.0mmol). The solution was allowed to warm to ambient temperature asstirring was continued for 20 hours. The reaction mixture was pouredinto water, acidified to pH 4 with acetic acid, and the resultantprecipitate was isolated by vacuum filtration to afford the titlecompound as an off-white solid (0.92 g), m.p. 221–224° C.

¹H NMR (400 MHz, DMSO-d₆): δ 6.40–7.60 (m, 7H), 7.56 (d, 1H), 7.98 (d,1H), 8.01 (d, 1H), 8.07 (d, 2H).

MS [EI, m/z]: 248 [M]⁺.

Anal. Calc'd. for C₁₇H₁₂O₂: C, 82.24, H, 4.87. Found: C, 81.90, H, 4.63.

Step C. [4-(Naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

N,N-Dimethylformamide (2 drops) was added to a solution of the4-naphthalen-1-yl-benzoic acid of Step B (0.60 g, 2.40 mmol) inanhydrous tetrahydrofuran (15 mL). Oxalyl chloride (0.34 g, 2.64 mmol)was added and the mixture was warmed to reflux. The resultant solutionwas cooled to ambient temperature before being evaporated to dryness togive the crude acid chloride as a golden solid, which was used withoutfurther purification. To a mixture of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.37 g, 2.00 mmol)and triethylamine (0.24 g, 2.40 mmol) in dichloromethane (5 mL), cooledin an ice bath, was added dropwise a solution of the crude acid chloridein dichloromethane (5 mL). The cooling bath was removed and afterstirring for 48 hours, the reaction mixture was washed sequentially withwater, saturated aqueous sodium bicarbonate, saturated aqueous sodiumchloride and 1 N sodium hydroxide. The dichloromethane solution wasdried with anhydrous magnesium sulfate, filtered, then evaporated todryness to yield a brown foam. Purification by flash chromatography onsilica gel eluting with hexane-ethyl acetate (4:1) resulted in a whitefoam (0.47 g). Treatment of the white foam with diethyl ether andsonication resulted in a white solid (0.37g), m.p. 169.5–171° C.

¹H NMR (400 MHz, DMSO-d₆): δ 5.32 (br, 4H), 5.93 (m, 1H), 5.97 (s, 1H),6.83 (m, 1H), 7.01 (d, 1H), 7.18 (m, 2H), 7.32, (t, 2H), 7.41, (d, 1H),6.45–7.60 (m, 5H), 7.93 (d, 1H), 7.97 (d, 1H)

MS [EI, m/z]: 414 [M]⁺.

Anal. Calcd. for C₁₇H₁₂O₂+0.4H₂O: C, 82.60, H, 5.45, N, 6.64. Found: C,82.71, H, 5.44, N, 6.54.

Step D.10-[(4-Naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

The title compound was prepared by treatment of[4-(naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step C with trichloroacetyl chloride, followed by basic hydrolysis ofthe intermediate trichloroacetate ester in the manner of Example 7, StepE.

Step E.10-[4-(Naphthalen-1-yl)-benzoyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

The title compound was prepared by the coupling the10-[4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step D, with 3-(methylaminomethyl)pyridine (1.25 equiv) in themanner of Example 7.

EXAMPLE 1010-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide

Step A. (4-Bromo-2-chloro-benzoyl)-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

N,N-Dimethylformamide (1 drop) was added to a solution of4-bromo-2-chlorobenzoic acid (2.20 g, 9.35 mmol) in anhydroustetrahydrofuran (20 mL). Oxalyl chloride (1.46 g, 11.46 mmol) was addedand the mixture was warmed to reflux. The resultant solution was cooledto ambient temperature before being evaporated to dryness to give thecrude acid chloride as a gold viscous liquid, which was used withoutfurther purification. To a mixture of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.44 g, 7.79 mmol)and triethylamine (0.95 g, 9.35 mmol) in methylene chloride (40 mL),cooled in an ice bath, was added dropwise a solution of the acidchloride in dichloromethane (20 mL). The cooling bath was removed andafter stirring for 22 hours, the reaction mixture was washedsequentially with water, saturated aqueous sodium bicarbonate, 0.5 Nhydrochloric acid and water. The dichloromethane solution was dried overanhydrous sodium sulfate, filtered, then evaporated to dryness to yieldan off-white foam. Purification by flash chromatography on silica geleluting with hexane-ethyl acetate (2:1) resulted in a white foam (3.02g), m.p. 77–80° C. This material was used as is in the next step.

¹H NMR (400 MHz, DMSO-d₆): δ 5.45 (br, 4H), 7.02 (t, 1H), 7.07 (td, 1H),7.14 (td), 7.32 (br, 1H), 7.38 (d, 2H), 7.60 (br, 1H).

MS [EI, m/z]: 400 [M]⁺.

Step B.(2-Chloro-4-naphthalen-1-yl-phenyl)-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

1-Naphthaleneboronic acid (0.52 g, 3.00 mmol) was added to a mixture of(4-bromo-2-chlorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone of Step A (1.27 g,3.15 mmol) and sodium carbonate (0.53 g, 4.98 mmol) in toluene (22.5mL), ethanol (4.5 mL) and water (9 mL). The resultant solution waspurged with nitrogen for 10 minutes, thentetrakis(triphenylphosphine)palladium (0.18 g, 0.06 mmol) was added. Thereaction mixture was heated to reflux for 76 hours. The solution wascooled to ambient temperature, then filtered through a pad of Celite,which was subsequently rinsed with ethyl acetate. The combined filtratewas diluted to 100 mL water/ethyl acetate (1:1). The aqueous layer wasextracted with ethyl acetate, and the combined organic layer was driedover anhydrous magnesium sulfate, filtered, and evaporated to dryness toyield a brown oil. Purification by flash chromatography on silica geleluting with hexane-ethyl acetate (5:1) resulted in a white solid whichwas dried under vacuum (0.62 g), m.p. 115–117.5° C.

¹H NMR (400 MHz, DMSO-d₆): δ 5.91 (t, 1H), 6.02 (br, 1H), 6.84 (br, 1H),7.14 (m, 2H), 7.24 (d, 1H), 7.34, (d, 1H), 7.95 (d, 1H), 7.98 (d, 1H).

MS [(+)ESI, m/z]: 449 [M+H]⁺.

Anal. Calcd. for C₂₉H₂₁ClN₂O+0.25 H₂O: C, 76.72, H, 4.79, N, 6.17. FoundC, 76.72, H, 4.53, N, 5.95.

Step C.10-{[2-Chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

Prepared by treatment of[2-chloro-4-(naphthalen-1-yl)-phenyl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanoneof Step B with trichloroacetyl chloride, followed by basic hydrolysis ofthe intermediate trichloroacetate ester in the manner of Example 5, StepD.

Step D.10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide

The title compound was prepared by the coupling the10-[2-chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C, with 4-(aminomethyl)pyridine (1.25 equiv) in the mannerof Example 1, Step G.

EXAMPLE 11{[10-(4-Methyl-napthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-4-yl)-1-piperazinyl]methanone

Step A. 4-(4-Methyl)-napthalen-1-yl-benzoic acid

To a mixture of 1-bromo-4-methyl napthalene (1.11 g, 5.00 mmol) and4-carboxyphenyl boronic acid (1.00 g, 6.00 mmol) in ethylene glycoldimethyl ether (20 mL) was added a solution of sodium carbonate (2.37 g,22.38 mmol) in water (18.75 mL). The resultant mixture was purged withnitrogen for 20 minutes before tetrakis(triphenylphosphine)palladium(0)(0.03 g, 0.02 mmol) was added. The reaction mixture was heated to refluxfor 68 hours. After the solution cooled to ambient temperature, thesolvent was removed in vacuo and the residue was acidified with 5 Nhydrochloric acid to produce an orange-brown solid that was isolated byvacuum filtration. This material was used without further purificationin the next step.

¹H NMR (300 MHz, DMSO-d₆): δ 2.70 (s, 3H), 7.57 (d, 2H), 8.07 (d, 2H).

Step B.[4-(4-Methyl-naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

N,N-Dimethylformamide (2 drops) was added to a solution of4-(4-methyl)-napthalen-1-yl-benzoic acid of Step A (0.90 g, 3.43 mmol),in anhydrous tetrahydrofuran (10 mL). Oxalyl chloride (0.52 g, 4.12mmol) was added and the mixture was warmed to reflux. The resultantsolution was cooled to ambient temperature before being evaporated todryness to give the crude acid chloride as a brown residue, which wasused without further purification. To a mixture of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.53 g, 2.86 mmol)and triethylamine (0.35 g, 3.43 mmol) in dichloromethane (10 mL), cooledin an ice bath, was added dropwise a solution of the crude acid chloridein dichloromethane (10 mL). The cooling bath was removed and afterstirring for 137 hours, the reaction mixture was washed sequentiallywith water, saturated aqueous sodium bicarbonate, and saturated aqueoussodium chloride. The dichloromethane solution was dried over anhydrousmagnesium sulfate, filtered, then evaporated to dryness to yield anamber oil. Purification by flash chromatography on silica gel elutingwith hexane-ethyl acetate (4:1) resulted in a tan foam (0.49 g).Treatment of this material with diethyl ether and sonication resulted inan off-white solid (0.37 g), m.p. 160–162° C.

¹H NMR (400 MHz, DMSO-d₆): δ 2.66 (s, 3H), 5.32 (br, 4H), 5.93 (t, 1H),5.97 (br, 1H), 6.83 (t, 1H), 7.01 (d, 1H), 7.22 (d, 2H), 7.28 (d, 2H),7.39 (t, 3H), 7.45 (m, 2H), 7.57 (m, 2H), 8.06 (d, 1H).

MS [(+)ESI, m/z]: 429 [M+H]⁺.

Anal. Calcd. for C₃₀H₂₄N₂O+0.13 H₂O: C, 83.63, H, 5.67, N, 6.50. Found:C, 83.63, H, 5.64, N, 6.43.

Step C.10-{[4-(4-Methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

Prepared from[4-(4-methyl-naphthalen-1-yl)-phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl]methanoneof Step B by treatment with trichloroacetyl chloride, followed by basichydrolysis of the intermediate trichloroacetate ester in the manner ofExample 1, Steps E and F.

Step D.{[10-(4-Methyl-napthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-4-yl)-1-piperazinyl]methanone

Prepared by the coupling of10-{[4-(4-methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C, with 1-(4-pyridinyl)-piperazine (1.2 equiv.) in themanner of Example 1.

EXAMPLE 1210-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-methyl-N-[2-(pyridin-4-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. (2-Methyl-2′-methoxy-[1,1′-biphenyl]-4-yl)carboxylic acid methylester

A mixture of 3-methyl-4-bromobenzoic acid methyl ester (2.0 g, 8.7mmol), 2-methoxyphenyl boronic acid (1.32 g, 8.7 mmol) and sodiumcarbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25mL), was purged with nitrogen for 1 hour. After addition of thetetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol),the reaction mixture was heated at 100° C. overnight. After cooling, thereaction was filtered through Celite and the cake washed with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification by flash chromatography on silica gel with a solventgradient from 20% to 50% dichloromethane in hexane gave 2.0 g of productas a colorless oil.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.09 (s, 3H), 3.70 (s, 3H), 3.85 (s, 3H),7.00–7.04 (m, 1H), 7.08–7.11 (m, 2H), 7.23 (d, 1H), 7.37–7.41 (m, 1H),7.77–7.79 (m, 1H), 7.83–7.84 (m, 1H).

MS [(+)APCI, m/z]: 257 [M+H]⁺.

Anal. Calcd. for C₁₆H₁₆O₃: C, 74.98, H, 6.29. Found: C, 74.06, H, 6.17.

Step B. (2-Methyl-2′-methoxy-[1,1′-biphenyl]-4-yl)carboxylic acid

The (2-methyl-2′-methoxy-[1,1′-biphenyl]-4yl)carboxylic acid methylester of Step A (1.9 g, 7.4 mmol) was dissolved in tetrahydrofuran (30mL) and 1 N sodium hydroxide (15 mL, 15 mmol) was added. The reactionmixture was heated at reflux overnight, then cooled and acidified with 2N hydrochloric acid. The aqueous layer was extracted with ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give 1.6 g of product as a whitesolid, m.p. 160–162° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.09 (s, 3H), 3.70 (s, 3H), 7.00–7.03 (m,1H), 7.08–7.10 (m, 2H), 7.20 (d, 1H), 7.36–7.40 (m, 1H), 7.75–7.78 (m,1H), 7.82 (s, 1H), 12.85 (br, 1H).

MS [(−)APCI, m/z]: 241 [M−H]⁻.

Anal. Calcd. for C₁₅H₁₄O₃: C, 74.36, H, 5.82. Found: C, 73.93, H, 5.71.

Step C.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanone

The (2-methyl-2′-methoxy-[1,1′-biphenyl]-4-yl)carboxylic acid of Step B(0.50 g, 2.06 mmol) was suspended in thionyl chloride (3 mL) and themixture heated at reflux for 30 minutes. After cooling, the thionylchloride was removed in vacuo. The residue was dissolved in toluene andconcentrated in vacuo to give the crude acid chloride as a brown oil.The acid chloride was then dissolved in dichloromethane (5 mL) andslowly added to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.57 g, 3.10 mmol)and N,N-diisopropylethyl amine (0.79 mL, 4.53 mmol) in dichloromethane(15 mL). After stirring for 1 hour, the reaction was quenched withwater. The organic layer was washed with 1 N hydrochloric acid, 1 Nsodium hydroxide and brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a yellow foam. Purificationby flash chromatography using a solvent gradient of 5 to 15% ethylacetate in hexane yielded a white foam which crystallized uponsonication in ethanol/hexane to give 0.42 g of the desired title productas a white solid, m.p. 133–135° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.93 (s, 3H), 3.65 (s, 3H), 4.80–5.40 (br,4H), 5.92–5.96 (m, 2H), 6.81–6.82 (m, 1H), 6.89–6.91 (m, 1H), 6.95–7.05(m, 5H), 7.16–7.25 (m, 3H), 7.31–7.35 (m, 1H), 7.47–7.49 (m, 1H).

MS [(+)ESI, m/z]: 409 [M+H]⁺.

Anal. Calcd. for C₂₇H₂₄N₂O₂: C, 79.39, H, 5.92, N, 6.86. Found: C,79.16, H, 5.87, N, 6.90.

Step D.2,2,2-Trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone

To a solution of(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanoneof Step C (1.5 g, 3.67 mmol) in dichloromethane (20 mL) was addedN,N-diisopropylethyl amine (1.28 mL, 7.35 mmol) followed by slowaddition of trichloroacetyl chloride (1.23 mL, 11.0 mmol). The reactionmixture was stirred overnight at room temperature then quenched withwater. The organic phase was washed with 0.1 N hydrochloric acidfollowed by water, then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a green oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane provided 2.1 g of title compound. The material was redissolvedin dichloromethane and evaporated to dryness to provide a yellow foam,which was used in the next step.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.94 (s, 3H), 3.65 (s, 3H), 5.25 (br, 2H),5.97 (br, 2H), 6.36–6.37 (m, 1H), 6.90–6.92 (m, 1H), 6.96–7.06 (m, 5H),7.15–7.23 (m, 2H), 7.26 (s, 1H), 7.32–7.36 (m, 1H), 7.44–7.47 (m, 2H).

MS [(+)APCI, m/z]: 553 [M+H]⁺.

Anal. Calcd. for C₂₉H₂₃Cl₃N₂O₃+0.13 C₄H₈O₂+0.13 CH₂Cl₂: C, 61.79, H,4.25, N, 4.86. Found: C, 60.43, H, 4.50, N, 4.80.

Step E.10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

To a solution of2,2,2-trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanoneof Step D (2.0 g, 3.6 mmol) in acetone (20 mL) was added 2.5 N sodiumhydroxide (2.9 mL, 7.25 mmol). After stirring overnight, the reactionmixture was acidified with 2 N hydrochloric acid (4.0 mL, 8.0 mmol) thenconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a brown solid. Triturationwith diethyl ether-hexane provided 1.4 g of the desired product as awhite solid, m.p.174–184° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.93 (s, 3H), 3.65 (s, 3H), 5.17 (br, 2H),5.94 (br, 2H), 6.09–6.10 (m, 1H), 6.77 (d, 1H), 6.89–7.06 (m, 6H),7.10–7.19 (m, 2H), 7.23 (s, 1H), 7.31–7.38 (m, 2H), 12.31 (br, 1H).

MS [(−)APCI, m/z]: 451 [M−H]⁻.

Anal. Calcd. for C₂₈H₂₄N₂O₄+0.10 C₄H₁₀O: C, 74.17, H, 5.48, N, 6.09.Found: C, 73.63, H, 5.68, N, 5.94.

Step F.10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-methyl-N-[2-(pyridin-4-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Prepared by treatment of10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step E, with 4-(2-methylaminoethyl)pyridine (1.2 equiv.) in themanner of Example 5, Step E.

EXAMPLE 13N-Methyl-10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide

Step A. 4-Iodo-2-methoxybenzoic acid methyl ester

4-Amino-2-methoxybenzoic acid methyl ester (3.0 g, 16.6 mmol) wassuspended in water (40 mL) and concentrated sulfuric acid (10 mL). Thesuspension was cooled in an ice/salt water bath, and an aqueous solution(10 mL) of sodium nitrite (1.26 g, 18.3 mmol) was added dropwise so thatthe temperature remained close to 0° C. After the addition, ahomogeneous, yellow-green solution was obtained. An aqueous solution (60mL) of potassium iodide (3.02 g, 18.2 mmol) and iodine (2.31 g, 9.1mmol) was then added dropwise, and the reaction stirred for anadditional 1 hour. The reaction mixture was then extracted with ethylacetate, the organic extracts were combined and washed with 1 N sodiumthiosulfate, 1 N sodium hydroxide and brine. After drying over anhydroussodium sulfate the solution was filtered and concentrated in vacuo togive 2.7 g of the title product as an orange oil which was used in thenext step.

¹H NMR (DMSO-d_(6, 400) MHz): δ 2.76 (s, 3H), 3.82 (s, 3H), 7.39 (s,2H), 7.48 (s, 1H).

MS [EI, m/z]: 292 [M]⁺.

Step B. 4-Iodo-2-methoxybenzoic acid

The 4-iodo-2-methoxybenzoic acid methyl ester of Step A (2.7 g, 9.24mmol) was dissolved in tetrahydrofuran (40 mL) and 1 N sodium hydroxide(20 mL, 20 mmol) was added. The reaction mixture was heated at refluxfor 3 hours, then cooled and concentrated in vacuo to give an orange oilthat was partitioned between ethyl acetate and 2 N hydrochloric acid.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give 2.5 g of title product as a yellow-orangesolid, m.p. 144–146° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 3.81 (s, 3H), 7.37 (s, 2H), 7.44 (s, 1H),12.72 (br, 1H).

MS [EI, m/z]: 278 [M]⁺.

Anal. Calcd. for C₈H₇IO₃+0.10 C₄H₈O₂: C, 35.17, H, 2.74. Found: C,35.37, H, 2.49.

Step C.10-(4-Iodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A suspension of 4-iodo-2-methoxybenzoic acid of Step B (2.5 g, 9.0 mmol)in thionyl chloride (10 mL) was heated at reflux for 1 hour. Aftercooling, the thionyl chloride was removed in vacuo. The residue wasdissolved in toluene and concentrated in vacuo to give the crude acidchloride as a brown solid. The acid chloride was then dissolved indichloromethane (10 mL) and slowly added to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.75 g, 9.5 mmol)and N,N-diisopropylethyl amine (3.4 mL, 19.5 mmol) in dichloromethane(20 mL). After stirring for 2 hours, the reaction was quenched withwater. The organic layer was washed with 1 N hydrochloric acid, 1 Nsodium hydroxide and brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a yellow foam. Purificationby flash chromatography on silica gel using a solvent gradient of 15 to25% ethyl acetate in hexane provided 3.6 g of title product as a whitefoam, which was redissolved in dichloromethane and evaporated to drynessprior to use in the next step.

¹H NMR (DMSO-d₆, 400 MHz): δ 3.55 (br, 3H), 4.80–5.32 (br, 4H),5.88–5.90 (m, 1H), 5.94 (s, 1H), 6.79 (s, 1H), 6.94 (s, 1H), 7.03 (t,1H), 7.09–7.13 (m, 3H), 7.20–7.22 (m, 1H), 7.36–7.38 (m, 1H).

MS [(+)ESI, m/z]: 445 [M+H]⁺.

Anal. Calcd. for C₂₀H₁₇IN₂O₂+0.10 C₄H₈O₂+0.13 CH₂Cl₂: C, 53.13, H, 3.92,N, 6.04. Found: C, 53.03, H, 3.65, N, 6.03.

Step D.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanone

A mixture of10-(4-iodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step C (1.8 g, 4.1 mmol), 2-methylphenyl boronic acid (0.55 g, 4.1mmol) and sodium carbonate (1.9 g, 17.9 mmol) in toluene:ethanol: water(20 mL:10 mL:10 mL) was purged with nitrogen for 1 hour. After additionof the tetrakis(triphenylphosphine) palladium(0) catalyst (0.24 g, 0.21mmol), the reaction mixture was heated at 100° C. overnight. Aftercooling, the reaction was filtered through Celite and the cake washedwith ethyl acetate. The organic layer was washed with water, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give abrown oil. Purification by flash chromatography on silica gel using asolvent system of 20% ethyl acetate in hexane provided 1.5 g of titleproduct as a white foam, which was redissolved in dichloromethane andevaporated to dryness in vacuo prior to use in the next step.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.08 (s, 3H), 3.54 (s, 3H), 4.80–5.30 (br,4H), 5.89–5.91 (m, 1H), 5.97 (s, 1H), 6.66 (s, 1H), 6.77–6.80 (m, 2H),6.93–7.01 (m, 2H), 7.09–7.10 (m, 2H), 7.19–7.24 (m, 3H), 7.36–7.38 (m,2H).

MS [(+)ESI, m/z]: 409 [M+H]⁺.

Anal. Calcd. for C₂₇H₂₄N₂O₂+0.10 CH₂Cl₂: C, 78.05, H, 5.84, N, 6.72.Found: C, 78.12, H, 5.13, N, 6.69.

Step E.2,2,2-Trichloro-1-{10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone

To a solution of(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanoneof Step D (1.36 g, 3.33 mmol) in dichloromethane (15 mL) was addedN,N-diisopropylethyl amine (1.2 mL, 6.89 mmol) followed by slow additionof trichloroacetyl chloride (1.1 mL, 9.85 mmol). The reaction mixturewas stirred overnight at room temperature then was quenched with water.The organic phase was washed with 0.1 N hydrochloric acid followed bywater, then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a green oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane gave 1.7 g of title product as a yellow foam.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.09 (s, 3H), 3.50 (s, 3H), 5.30 (br, 2H),5.87 (br, 2H), 6.37–6.38 (m, 1H), 6.64 (s, 1H), 6.82–6.83 (m, 1H),6.90–6.92 (m, 1H), 6.97–6.99 (m, 1H), 7.10–7.12 (m, 2H), 7.20–7.25 (m,4H), 7.35–7.37 (m, 1H), 7.44–7.46 (m, 1H).

MS [(+)APCI, m/z]: 553 [M+H]⁺.

Anal. Calcd. for C₂₉H₂₃Cl₃N₂O₃+0.20 C₄H₈O₂+0.40 H₂O: C, 61.85, H, 4.42,N, 4.84. Found: C, 61.50, H, 4.07, N, 4.72.

Step F.10-[(3-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid

To a solution of2,2,2-trichloro-1-{10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanoneof Step E (1.6 g, 2.9 mmol) in acetone (20 mL) was added 2.5 N sodiumhydroxide (2.3 mL, 5.8 mmol). After stirring overnight, the reaction wasacidified with 2 N hydrochloric acid (3.2 mL, 6.4 mmol) thenconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The layers were separated, and the organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive a brown solid. Trituration with diethyl ether/hexane provided 1.2 gof desired product as an off-white solid, m.p. 201–204° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 2.09 (s, 3H), 3.48 (s, 3H), 5.20 (br, 2H),5.85 (br, 2H), 6.12 (s, 1H), 6.62 (s, 1H), 6.73 (d, 1H), 6.79–6.87 (m,2H), 6.91–6.95 (m, 1H), 6.99–7.03 (m, 1H), 7.06–7.12 (m, 1H), 7.18–7.25(m, 4H), 7.39 (br, 1H), 12.31 (br, 1H).

MS [(+) ESI, m/z]: 453 [M+Na]⁺.

Anal. Calcd. for C₂₈H₂₄N₂O₄+0.10 C₄H₁₀O+0.15 C₄H₈O₂: C, 73.61, H, 5.58,N, 5.92. Found: C, 73.23, H, 5.49, N, 6.06.

Step GN-Methyl-10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide

Prepared from the10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step F and methyl-pyridin-3ylmethyl-amine (1.1 equiv.) in themanner of Example 5.

EXAMPLE 147,8-Dimethoxy-{10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-yl}[4-(pyridin-2-yl)-1-piperazinyl]methanone

Step A.1-[(4,5-Dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde

To a suspension of sodium hydride (0.724 g, 60% suspension in oil) inN,N-dimethyl formamide (50 mL) was added pyrrole 2-carboxaldehyde (1.7g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes. Itwas then cooled to 0° C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g,1 equiv) was added dropwise over 20 minutes. After the addition, thereaction mixture was stirred at room temperature for 3 hours. It wasthen diluted with ethyl acetate (450 mL), washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated to dryness. Thecrude product was triturated with water, filtered and washed with water.This material was dried over anhydrous potassium carbonate in vacuo toprovide the title compound as a yellow crystalline solid (4.97 g), m.p.109–112° C., which was used in the next step.

Step B. 7,8-Dimethoxy 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of the1-[(4,5-dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde ofStep A (4.97 g), acetic acid (0.5 mL), magnesium sulfate (0.5 g) and 10%palladium on charcoal (0.5 g) in ethyl acetate (50 mL) was hydrogenatedovernight at atmospheric pressure. The reaction was then filteredthrough Celite and the solvent removed in vacuo to give the crude titlecompound as an amber foam (3.2 g) which was used in the next stepwithout further purification.

Step C.7,8-Dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanone

To a solution of7,8-dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of StepB (3.20 g) in dichloromethane (20 mL) was added 3-methylbenzoyl chloride(3.4 g, 1.1 equiv) and triethylamine (2.0 g, 1.5 equiv) and the mixturewas stirred at room temperature overnight. The solvent was then removedin vacuo and the residue chromatographed on silica gel eluting with asolvent gradient from 5 to 50% of ethyl acetate in petroleum ether toprovide the title compounds as a yellow crystalline solid (3.5 g), m.p.165–168° C.

¹H NMR (CDCl₃, 200 MHz): δ 2.30 (s, 3H), 3.55 (br, 3H), 3.85 (s, 3H),5.1 (br, 4H), 6.05 (br, 1H), 6.1 (t, 1H), 6.3 (br, 1H), 6.65 (t, 1H),6.8 (s, 2H), 7.3 (s, 2H).

MS [(+)ESI, m/z]: 442 [M +H]⁺.

Step D.7,8-Dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]-[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone

The7,8-dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanoneof Step C (1.0 g) was reacted with 2-trifluoromethylphenyl boronic acid(0.645 g, 1.5 equiv.), potassium phosphate (0.964 g, 2.0 equiv.) and acatalytic amount (0.050 g) of tetrakis(triphenylphosphine) palladium(0)in refluxing dioxane (10 mL) under nitrogen for 24 hours. The reactionwas then cooled to room temperature, filtered through Celite, and thesolvent removed in vacuo. The residue was dissolved in dichloromethaneand the solution was washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated to dryness. The crude product soobtained was purified by chromatography on silica gel eluting with 5%ethyl acetate/dichloromethane to provide the title product (1.0 g) as awhite crystalline solid, m.p. 187–188° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.85 (s, 3H), 3.40 (s, 3H), 3.70 (s, 3H),6.20 (br, 4H), 5.92 (t, 1H), 5.96 (s, 1H), 6.56 (s, 1H), 6.77 (t, 1H),6.90 (m, 1H), 7.05 (m, 2H), 7.20 (d, 1H), 7.30 (s, 1H), 7.58 (t, 1H),7.68 (t, 1H), 7.80 (d, 1H).

MS [(+)APCI, m/z]: 507 [M+H]⁺.

Anal. Calcd. for C₂₉H₂₅F₃N₂O₃: C, 68.77, H, 4.97, N, 5.53. Found: C,68.85, H, 5.05, N, 5.43.

Step E.7,8-Dimethoxy-{10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-yl}[4-(pyridin-2-yl)-1-piperazinyl]methanonedihydrochloride salt

A solution of7,8-dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanoneof Step D (0.31 mmol), diphosgene (1.1 equiv.) and triethylamine (1.5equiv.) in dichloromethane (5 mL) was stirred at room temperatureovernight. The solvent was removed in vacuo and the residue wasdissolved in dichloromethane (5 mL). To the solution was addedtriethylamine (1.5 equiv.) and 1-(2-pyridinyl)piperazine (1.5 equiv.)The reaction mixture was washed with water, dried over anhydrousmagnesium sulfate, filtered and evaporated to dryness. The residue wasfirst chromatographed on silica gel eluting with a solvent gradient ofmethanol in ethyl acetate to provide the title compound as a foam.

Treatment of a solution of the free base in ethanol with anhydroushydrogen chloride in dioxane followed by removal of the solvent providedthe dihydrochloride salt.

EXAMPLE 1510-[(6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(pyridin-2-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. 2-Chloro-2′-ethoxy-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid

To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid ofExample 15, Step A (0.500 g, 1.6 mmol) in N,N-dimethylformamide (30 mL)was added 2-ethoxy phenyl boronic acid (0.8 g, 4.8 mmol) and potassiumcarbonate (2.04 g, 14.7 mmol). This mixture was purged with nitrogen andthen treated with a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (0.093 g, 0.08 mmol). The reaction was heated to refluxovernight, cooled, acidified with 2 N hydrochloric acid and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered, and evaporated to yield the titleacid which was used in the next step without further purification.

Step B.10-{[6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of the 2-chloro-2′-ethoxy-5-methoxy[1,1′-biphenyl]-4-carboxylic acid of Step A (0.491 g) in tetrahydrofuran(5 mL) containing a catalytic amount of N,N-dimethyl formamide was addeddropwise thionyl chloride (0.210 g, 1.76 mmol). The reaction mixture wasstirred for 2 hours, and then added dropwise to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.294 g, 1.60 mmol)in tetrahydrofuran (5 mL) containing triethylamine (0.357 g, 3.52 mmol).The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Trituration of the residue withmethanol provided the title compound as an off-white solid, 99.24% pureby analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase70/30 acetonitrile/water containing 0.1% phosphoric acid], m.p. 213–215°C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.11, (t, 3H), 3.51 (s, 3H), 3.92 (q, 2H),5.17–5.20 (br, m, 3H), 5.89 (t, 1H), 5.97 (s, 1H), 6.67–7.55 (m, 10H).

MS [(+)APCI, m/z]: 473 [M+H]⁺.

Anal. Calcd. for C₂₈H₂₅ClN₂O₃: C, 71.11, H, 5.33, N, 5.92. Found: C,70.31, H, 5.27, N, 5.79.

Step C.10-{[6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

Prepared by treatment of10-{[6-chloro-3-methoxy-2′-ethoxy-1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step B with trichloroacetyl chloride, followed by basic hydrolysis ofthe intermediate trichloroacetate ester in the manner of Example 1,Steps E and F.

Step D.10-[(6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(pyridin-2-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Prepared by coupling the10-{[6-chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C with 2-(aminomethyl)pyridine (1.25 equiv.) in the mannerof Example 1.

EXAMPLE 1610-[(6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-yl)carbonyl]-N-methyl-N-[2-(pyridin-2-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. 2-Chloro-2′-fluoro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid

To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid ofExample 15, Step A (3.72 g, 19.1 mmol) in N,N-dimethylformamide (20 mL)was added 2-fluorophenyl boronic acid (5.0 g, 35.7 mmol) and potassiumcarbonate (14.8 g, 107 mmol). This mixture was purged with nitrogen andthen treated with a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (0.688 g, 0.59 mmol). The reaction was heated to refluxovernight, cooled, acidified with 2 N hydrochloric acid and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered, and evaporated to dryness. Theresidue was flash chromatographed on acid washed silica using a 10 to50% gradient of diethyl ether in hexane to provide the desired titlecompound (3.8 g) as a white solid.

¹H NMR (DMSO-d₆, 400 MHz) δ 3.83 (s, 3H), 7.15 (s, 1H), 7.30–7.35 (m,2H), 7.42 (m, 1H), 7.48–7.54 (m, 1H), 7.74 (s, 1H).

MS [(+)ESI, m/z]: 298 [M+NH₄]⁺.

Anal. Calcd. for C₁₄H₁₀ClFO₃: C, 59.91, H, 3.59. Found: C, 59.79, H,3.35.

Step B.10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of2-chloro-2′-fluoro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step A(3.80 g, 13.5 mmol) in tetrahydrofuran (20 mL) containing a catalyticamount of N,N-dimethylformamide was added dropwise thionyl chloride(1.77 g, 14.9 mmol). The reaction mixture was stirred for 2 hours, andthen added dropwise to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.49 g, 13.5 mmol)in tetrahydrofuran (20 mL) containing triethylamine (3.0 g, 29.8 mmol).The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Recrystallization of the residuefrom ethyl acetate/heptane provided the title compound as a pale yellowsolid, m.p. 192–194° C., found to be 99.99% pure by analytical HPLC[Primesphere C-18 column (2.0×150 mm); mobile phase: gradient from 10 to100% of acetonitrile/water containing 0.1% phosphoric acid, 7 minutegradient].

¹H NMR (DMSO-d₆, 400 MHz): δ 3.55 (s, 3H), 5.19 (br m, 2H), 5.90 (t,1H), 5.96 (s, 1H), 6.80 (s, 2H), 7.07–7.63 (m, 10H).

MS [(+)ESI, m/z]: 447 [M+H]⁺.

Anal. Calcd. for C₂₆H₂₀ClFN₂O₂+H₂O: C, 69.60, H, 4.54, N, 6.24. Found:C, 69.39, H, 4.41, N, 6.20.

Step C.10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

A solution of the10-{[6-chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step B (3.02 g, 6.76 mmol) in dichloromethane (35 mL) was treatedwith N,N-diisopropylethyl amine (0.960 g, 7.43 mmol) and stirred for 10minutes. Trichloroacetyl chloride (1.47 g, 8.10 mmol) was then addeddropwise. The reaction mixture was stirred overnight, diluted withdichloromethane, washed with 0.1 N hydrochloric acid, saturated aqueoussodium bicarbonate, and brine. The organic phase was dried overanhydrous magnesium sulfate, filtered, and evaporated to yield the crudetrichloroketone intermediate which without further purification, wasdissolved in acetone and treated with an excess of 1 N sodium hydroxideThe mixture was stirred overnight, and then diluted with isopropylacetate and acidified with 1 N hydrochloric acid. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andevaporated to dryness. The solid residue was triturated with methanol toprovide the title compound (2.95 g) as a beige solid, m.p. 207–208° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 3.49 (br, 3H), 6.12 (d, 1H), 6.72 (d, 1H),6.77 (s, 1H), 7.01 (d, 2H), 7.09 (m, 1H), 7.26 (m, 4H), 7.45 (m, 2H),7.61 (br, 1H), 12.35 (br, 1H).

MS [(+)APCI, m/z]: 491 [M+H]⁺.

Anal. Calcd for C₂₇H₂₀ClFN₂O₄: C, 66.06, H, 4.11, N, 5.71. Found: C,65.68, H, 4.24, N, 5.48.

Step D.10-[(6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-yl)carbonyl]-N-methyl-N-[2-(pyridi-2-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Prepared by the coupling of the[(6-chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C with methyl-(2-pyridin-2-yl-ethyl)-amine (1.25 equiv.),in the manner of Example 1.

EXAMPLE 1710-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide

Step A.(6-Chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (100mmol) and N,N′-diisopropylethyl amine (130 mmol) in dichloromethane (500mL) was cooled to 0° C. 6-Chloronicotinoyl chloride (130 mmol) was addeddropwise under nitrogen. The solution was stirred for one hour as itreturned to room temperature. The reaction mixture was filtered througha sica gel pad, washed with 0.5 N sodium hydroxide and water, dried overanhydrous magnesium sulfate. The solution was again filtered through asilica gel pad and evaporated to dryness in vacuo. The residual oilcrystallized from diethyl ether to provide the title compound as acolorless crystalline solid, m.p. 165–167° C.

¹HNMR 9400 Mhz, DMSO-d₆): δ 5.35 (br, 4H), 5.91 (t, 1H), 5.97 (s, 1H),6.83 (t, 1H), 7.0 (br d, 1H), 7.18 (t, 1H), 7.19 (t, 1H), 7.39 (d, 1H),7.46 (dd, 1H), 7.71 (d, 1H), 8.26 (s, 1H).

MS [EI, m/z]: 323 [M]⁺.

Anal. Calcd. for C₁₈H₁₄ClN₃O: C, 66.77, H, 4.36, N, 12.98. Found: C,65.91, H, 4.18, N, 12.69.

Step B.[6-(Naphthalen-1-yl)-pyridin-3-y]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

A suspension of(6-chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo{2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step A (0.645 g, 1.9 mmol) and naphthalene boronic acid (0.372 g, 2.1mmol) in a mixture of toluene (1.2 mL), ethanol (2 mL) and 1M aqueoussodium carbonate (0.4 mL) was sparged with nitrogen for 10 minutes. Tothis was added palladium(I) acetate (0.026 g, 0.1 mmol). The mixture washeated at reflux under a static pressure of nitrogen for 48 hrs. Thereaction was diluted with ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium bicarbonate then water. The samplewas dried over anhydrous magnesium sulfate, filtered and concentrated invacuo to a brown oil. Flash chromatography of the residue on silica geleluting with 20–50% ethyl acetate in hexane, yielded 0.180 g of a solidwhich was recrystallized from chloroform to provide the title compoundas off white crystals, m.p. 155–158° C.

¹H NMR (400 MHz, DMSO-d₆): δ 5.40 (br, 4H), 5.93(m, 1H), 5.99 (s, 1H),6.84 (s, 1H), 7.08(br d, 1H), 7.16 (t, 1H), 7.23 (t, 1H), 7.52 (m, 6H),7.84(d, 2H), 7.98 (dd, 2H), 8.55 (s, 1H).

MS [(+)ESI, m/z]: 416 [M+H]⁺.

Anal. Calcd. for C₂₈H₂₁N₃O+0.5 H₂O: C, 79.22, H, 5.23, N, 9.90. Found:C, 79.08, H, 4.94, N, 9.73.

Step C.10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1.4]benzodiazepine-3-carboxylicacid

Prepared from[6-(naphthalen-1-yl)-pyridin-3-yl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step B by treatment with trichloroacetyl chloride, followed by basichydrolysis of the intermediate trichloroacetate ester in the manner ofExample 1, Steps E and F.

Step D.10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide

Prepared by the coupling of10-{[6-(naphthalen-1-yl)-pyridin-3-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1.4]benzodiazepine-3-carboxylicacid of Step C, and 4-(aminomethyl)pyridine (1.25 equiv) in the mannerof Example 1.

EXAMPLE 1810-[(6-Phenyl-pyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A.10-(Methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (5mmol) and N,N-diisopropylethyl amine (12 mmol) in dichloromethane (100mL) was cooled to 0° C. and treated dropwise withtrichloroacetylchloride (12 mmol) in dichloromethane (20 mL). Thesolution was maintained at 0° C. for two hours and then allowed to warmto room temperature overnight. The solution was then treated withmethanol (25 mL) and stirring was continued for 2 hours. The solutionwas washed with 0.1N hydrochloric acid, water and brine, dried overanhydrous magnesium sulfate, filtered and concentrated to yield thetitle compound as a white solid, m.p. 153–154° C. (dec.).

Anal. Calcd. for C₁₅H₁₄N₂O₄+0.06 C₄H₈O₂+0.07 C₃H₆O: C, 62.77, H, 5.08,N, 9.48. Found: C, 62.26, H, 5.22, N, 9.37.

Step B.10-(Methoxycarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

The title compound was prepared by coupling the10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step A with 3-(aminomethyl)pyridine (1.2 equiv.), in the mannerof Example 1, Step G.

Step C.N-(3-Pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

A solution of10-(methoxycarbonyl)-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide(5 mmol) of Step B in methanol (50 mL) was treated with potassiumcarbonate and stirred at room temperature overnight. Water was thenadded to the solution and the pH adjusted to 6 with 6N hydrochloricacid. The solution was extracted with ethyl acetate, and the combinedorganic layers were dried over anhydrous magnesium sulfate, andevaporated to dryness. The residual oil was triturated with ethylacetate and hexane to yield the title compound as a powder.

Step D.10-[(6-Phenyl-pyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

A solution of 6-phenyl-nicotinyl chloride (6 mmol) [prepared by themethod of Ogawa (Ogawa et al WO 9534540)] in dichloromethane (20 mL) wasadded dropwise to a cold (0° C.) solution ofN-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamideof Step C (5 mmol) and N,N-diisopropylethyl amine (6 mmol) indichloromethane (100 mL). The solution was stirred at 0° C. for 2 hoursand then allowed to warm to room temperature overnight. The solution waswashed with pH 6 buffer, and brine, dried over anhydrous sodium sulfate,filtered and concentrated. The residue was chromatographed on silica gelusing 5% methanol in chloroform containing 0.5% ammonium hydroxide, toprovide the title compound.

EXAMPLE 19[3-Methyl-4-(pyridin-4-yl)-phenyl]-{3-[4-(pyridin-2-yl)-piperazin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone

Step A. (4-Bromo-3-methylphenyl)-[10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepin-10-yl]methanone

A solution of 4-bromo-3-methyl benzoic acid (4.3 g, 2 mmol) in drytetrahydrofuran (100 mL) was cooled to 0° C. under nitrogen. To this wasadded N,N-dimethylformamide (50 μL) followed by oxalyl chloride (2.2 mL,25 mmol) dropwise to control the gas evolution. When the gas evolutionceased, the mixture was warmed to reflux for 5 minutes then cooled toroom temperature and concentrated in vacuo. The sample was treated withtetrahydrofuran and evaporated to dryness (twice) to yield the crudeacid chloride as an orange oil. A solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3.60 g, 20 mmol) andHünig's base (4.35 mL, 25 mmol) in dichloromethane was cooled to 0° C.,and a solution of the crude acid chloride in dichloromethane (25 mL) wasadded dropwise. The mixture was stirred overnight at room temperature,washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonateand brine. The solution was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to yield a solid (8.01 g) which waspurified by flash chromatography on silica gel eluting with 20% ethylacetate in hexane to provide the title compound (6.03 g) as a whitesolid.

¹H NMR (300 MHz, CDCl₃): δ 2.30 (s, 3H), 5.20 (br, 4H), 6.05 (d, 2H),6.70 (s, 1H), 6.85 (br, 2H), 7.17 (m, 2H), 7.30 (m, 2H), 7.37 (d, 1H).

Step B.[3-Methyl-4-(pyridin-4-yl)phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

A suspension of(4-bromo-3-methylphenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step A (1.14 g, 2.9 mmol), pyridine-4-boronic acid (0.368 mg, 2.9mmol) and sodium carbonate (0.760 g, 7.2 mmol) in a mixture of toluene(30 mL), water (10 mL), and ethanol (5 mL) was sparged with nitrogen for15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0)(0.027 g) and the mixture was heated to reflux under a static pressureof nitrogen. After 24 hours additional boronic acid (0.128 mg, 1 mmol)and sodium carbonate (0.116 g) were added and the heating was continuedfor 24 hours. Additional catalyst (0.012 g) was added and heating wascontinued for another 24 hours. The mixture was partitioned betweenethyl acetate and hexane. The water layer was washed twice with ethylacetate and the combined organic layers were dried over anhydrousmagnesium sulfate and stripped to a solid. Flash chromatography of theresidue on silica gel eluting with 30% ethyl acetate in hexane provideda solid which was recrystallized from ethyl acetate/hexane to providethe title compound (0.254 g) as tan plates m.p. 208–210° C.

¹H NMR (400 MHz, DMSO-d₆): δ 1.75 (s, 3H), 1.77 (s, 3H), 5.18 (br, 4H),5.89 (s, 2H), 6.05 (br, 1H), 6.08 (t, 1H), 6.69 (t, 1H), 6.85 (br, 1H),7.03 (br, 3H), 7.16 (t, 1H), 7.35 (d, 1H).

MS [EI, m/z]: 379 [M]⁺.

Anal. Calcd. for C₂₅H₂₁N₃O+0.5 H₂O: C, 77.30, H, 5.71, N, 10.82. Found:C, 77.01, H, 5.37, N, 10.68.

Step C.10-[3-Methyl-4-(pyridin-4-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepine-3-carboxylic acid

To a stirred solution of[3-methyl-4-(pyridin-4-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step B (5 mmol) and N,N-diisopropylethyl amine (12 mmol) indichloromethane (200 mL) cooled to 0° C. was added dropwise a solutionof trichloroacetyl chloride (12 mmol) in dichloromethane. Thetemperature was maintained at 0° C. until the addition was complete. Thereaction was stirred overnight as it warmed to room temperature. Thesolution was then washed with 10% aqueous sodium bicarbonate and theorganic layer was dried, concentrated and filtered through a pad ofsilica gel with 1:1 ethyl acetate/hexane containing 0.1% acetic acid.The filtrate was concentrated in vacuo and the residue was dissolved inacetone and 1N sodium hydroxide (2:1,v/v) and stirred at roomtemperature for 1 hour and then the pH was adjusted to pH 4 with glacialacetic acid. The solution was concentrated to one half the volume invacuo and the residue extracted with ethyl acetate. The combined organiclayers were dried and evaporated to an oil which was triturated withhexane to yield a solid (0.98 g).

Step D.[3-Methyl-4-(pyridin-4-yl)-phenyl]-{3-[4-(pyridin-2-yl)-piperazin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone

The title compound was obtained from the10-[3-methyl-4-(pyridin-4-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepine-3-carboxylicacid of Step C and 1-(pyridin-2-yl)piperazine ((1.2 equiv.), in themanner of Example 1.

EXAMPLE 2010-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-8-[(piperidin-1-yl)carbonyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. [4-(2-Formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acidmethyl ester

To a suspension of sodium hydride (8.1 g, 60% suspension in oil) inN,N-dimethylformamide (25 mL) was added dropwise over 15 minutes asolution of pyrrole 2-carboxaldehyde (9.1 g, 1 equiv.) inN,N-dimethylformamide (25 mL). After the addition, the reaction mixturewas stirred for 30 minutes and then cooled to 0° C. A solution of4-bromomethyl-2-nitrobenzoic acid (25.0 g, 1 equiv.) inN,N-dimethylformamide (50 mL) was added dropwise over 20 minutes. Afterthe addition, the reaction mixture was stirred at room temperature for 1hour and then iodomethane (1.2 eq.) was added. The reaction mixture wasstirred at room temperature overnight and diluted with water (200 mL).The solid was filtered, washed with water and dried over anhydrouspotassium carbonate in vacuo at 50° C. to provide the crude titlecompound as a brown solid (26 g) which was used as such in the nextstep.

Step B.10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylicacidmethyl ester

To a stirred solution of tin(II) chloride dihydrate (23 g, 3.5 eq) in 2N hydrochloric acid (106 mL) was added the[4-(2-formyl-1H-pyrrole-1-yl)methyl]-3-nitro]-benzoic acid methyl esterof Step A (8 g). Methanol (200 mL) was then added to this solution andthe reaction mixture was stirred at 40° C. for 2 hours. The reaction wasthen cooled to room temperature, quenched by the addition of saturatedaqueous sodium carbonate (20 mL) and filtered through Celite. The filterpad was washed with methanol and hot ethyl acetate. The filtrate andwashings were combined, concentrated in vacuo to a volume of 300 mL andextracted with ethyl acetate. The combined extracts were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to avolume of 200 mL. Acetic acid (1 g) and 10% palladium on charcoal (1.5g) were added and the mixture was hydrogenated overnight at atmosphericpressure. The reaction was then filtered through Celite and the solventremoved in vacuo to give a dark brown crystalline solid (16.4 g). Thiswas dissolved in dichloromethane and filtered through a silica padeluting with dichloromethane to provide the title compound as a yellowcrystalline solid (11.7 g). Recrystallization from 1,2-dichloroethaneyielded a yellow crystalline solid (5.7 g), m.p. 198–200° C.

¹H NMR(CDCl₃, 200 MHz): δ 3.95 (s, 3H), 4.50 (s, 2H), 5.20 (s, 2H), 6.05(t, 2H), 6.70 (t, 1H), 7.05 (d, 1H), 7.15 (s, 1H), 7.20 (d, 1H), 7.30(s, 1H).

Step C. Methyl10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-8-carboxylate

To a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acidmethyl ester of Step B (1.64 g) in 1,2-dichloroethane (25 mL) was added4-(2-trifluoromethylphenyl)-3-methylbenzoyl chloride (2.0 g, 1.1 eq)prepared in the manner of Example 1, Step D and triethylamine (1.0 g)and the mixture was stirred at room temperature overnight. The solventwas then removed in vacuo and the residue chromatographed on silica geleluting with 10% ethyl acetate in petroleum ether to provide the titlecompound as a white crystalline solid, m.p. 180–182° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.80 (s, 3H), 3.70 (s, 3H), 5.0–5.5 (br,4H), 5.80 (t, 1H), 6.00 (s, 1H), 6.85 (t, 1H), 6.90 (s, 1H), 7.00 (br,1H), 7.20 (d, 1H), 7.35 (s, 1H), 7.60 (t, 2H), 7.70 (t, 2H), 7.75 (d,1H), 7.80 (d, 1H).

MS [(+)ESI, m/z]: 505 [M+H]⁺.

Anal. Calcd. for C₂₉H₂₃F₃N₂O₃: C, 69.04; H, 4.60; N, 5.55. Found: C,67.76; H, 4.30; N, 5.40.

Step D.10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylicacid sodium salt

To a stirred solution of methyl10-{[2-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1.4]benzodiazepine-8-carboxylateof Step C (0.200 g) in ethanol (5 mL) was added 2.5 N sodium hydroxide(4 mL). The reaction mixture was then stirred overnight at roomtemperature and the solvent removed in vacuo. The residue was acidifiedwith 2 N hydrochloric acid and extracted with diethyl ether. Thecombined extracts were dried over anhydrous magnesium sulfate andfiltered, and the the filtrate evaporated to dryness. The residue wasdissolved in anhydrous ethanol and treated with 2.5 N sodium hydroxide(1.0 equiv.). After stirring for 30 minutes at room temperature, thesolvent was removed in vacuo to provide the title compound sodium saltas a white solid, m.p. 210° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.85 (s, 3H), 5.20 (br, 3H), 5.90 (s, 2H),6,80 (t, 1H), 6.90–7.80 (m, 11H).

MS [(+)APCI, m/z]: 491 [M+H]⁺.

Anal. Calcd. for C₂₈H₂₁F₃N₂O₃Na+H₂O: C, 63.27; H, 4.36; N, 5.27. Found:C, 63.04; H, 4.21; N, 4.99.

Step E.8-[(Piperidin-1-yl)carbonyl]-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

Prepared by coupling of10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylicacid of Step D with piperidine, in the manner of Example 1, Step G.

Step F.10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-8-[(piperidin-1-yl)carbonyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Prepared by treatment of8-[(piperidin-1-yl)carbonyl]-{[2-methyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step E with diphosgene (1.1 equiv.) and triethylamine (1.5 equiv.)followed by 4-(aminomethyl)pyridine (1.5 equiv.) in the manner ofExample 14, Step E.

EXAMPLE 2110-[(3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Step A. 2,5-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicacid

A suspension of 4-bromo-2,5-dimethoxybenzoic acid [prepared in themanner of Bortnik et al., Zh. Org. Khim. 8, 340 (1972)] (2.43 g, 9mmol), 2-trifluoromethylphenyl boronic acid (5.3 g, 28 mmol), andpotassium carbonate (6.21 g, 60 mmol) in dioxane (40 mL) was spargedwith nitrogen and treated with tetrakis(triphenylphosphine)palladium(0)(0.328 g, 0.2 mmol). The mixture was heated to reflux for 48 hours,cooled, acidified with 1N hydrochloric acid and extracted with ethylacetate The extracts were dried over anhydrous magnesium sulfate,filtered and stripped to a solid which was used as such in the nextstep.

¹H NMR (300 MHz, CDCl₃): δ 3.90 (s, 3H), 4.05 (s, 3H), 7.30 (d, 1H),7.70 (s, 1H).

Step B.10-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

The title compound was prepared in the manner of Example 19, Step Ausing 2,5-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acidof Step A (1.63 g, 5 mmol), oxalyl chloride (700 μL, 8 mmol),N,N-dimethylformamide (10 μL),10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.93 g, 5 mmol) andHünig's base (1.78 ml, 10 mmol). Flash chromatography over silica gelusing a solvent gradient from 30% ethyl acetate in hexane to 100% ethylacetate provided the title compound (0.900 g) as a solid.Recrystallization from acetone/hexane yielded white needles, m.p.210–213° C.

¹H NMR (400 MHz, DMSO-d₆: δ3.41 (s, 3H), 3.56 (s, 3H), 5.21 (br, 4H),5.90 (t, 1H), 5.96 (s, 1H), 6.50 (s, 1H), 6.80 (s, 1H), 7.00 (s, 2H),7.07 (s, 1H), 7.10 (t, 1H), 7.18 (d, 1H), 7.37 (d, 1H), 7.53 (t, 1H),7.62 (t, 1H), 7.73 (d, 1H).

MS [(+)ESI, m/z]: 493 [M+H]⁺.

Anal. Calcd. for C₂₈H₂₃ F₃N₂O₃: C, 68.29, H, 4.71; N, 5.69. Found: C,67.98, H, 4.66, N, 5.61.

Step C.10-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxylicacid

Prepared from10-{[3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step B and trichloroacetyl chloride, followed by basic hydrolysis ofthe intermediate trichloroacetate ester, in the manner of Example 1,Steps E and F.

Step D.10-[(3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

Prepared from10-{[(3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxylicacid of Step C and methyl-pyridin-3-ylmethyl-amine (1 equiv.) in themanner of Example 5, Step E.

EXAMPLE 2210-[(2′-Chloro-2-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-2-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide

To a solution of10-{[2-methoxy-2′-chloro[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (0.230 g, 0.54 mmol) [prepared from trifluoromethanesulfonic acid4-formyl-2-methoxy-phenyl ester of Example 7, Step A and 2-chlorophenylboronic acid, in the manner of Example 7, Steps B–E], inN,N-dimethylformamide (15 mL) is added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.120 g,0.625 mmol) and 1-hydroxybenzotriazole (0.625 mmol). To the homogeneoussolution was added methyl-pyridin-2-ylmethyl-amine (0.625 mmol) and thestirring was continued at room temperature overnight. At the end of thistime the solution was poured into water and extracted with ethylacetate. The combined extracts were washed with water, dried andconcentrated and the residue was chromatographed on silica gel, elutingwith 95:5 chloroform:methanol. The pure fractions were concentrated, andthe residue azeotroped and triturated several times with hexane to yieldthe title product.

EXAMPLE 23 {[[3-(Pyridin-2-ylmethyl)amino]carbonyl]-4H-10H-3a,5,9-triaza-benzo[f]azulen-9-yl}-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone

Step A. 2-Chloromethyl-pyridine-3-carboxylic acid methyl ester

A solution of methyl 2-methyinicotinate (20.0 g, 0.132 mol) andtrichloroisocyanuric acid (46.0 g, 0.198 mol) in dichloromethane (100mL) was stirred at room temperature overnight. The reaction mixture wasthen washed with saturated aqueous sodium carbonate and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and the solvent evaporated in vacuo to provide the titlecompound as a yellow liquid (11.2 g), which is used as such in the nextstep

Step B. 2-(2-Formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acid methylester

To a suspension of sodium hydride (5.8 g, 0.12 mol), was in dryN,N-dimethyl formamide (25 mL) was added slowly under nitrogen asolution of pyrrole 2-carboxaldehyde (10.5 g, 0.11 mol) inN,N-dimethylformamide (10 mL), and the reaction mixture was stirred atroom temperature for 30 minutes. The reaction was then cooled to 5° C.and 2-chloromethyl-pyridine-3-carboxylic acid methyl ester of Step A wasadded slowly, the temperature being maintained at or below 20° C. Afterthe addition was complete, the reaction was stirred at room temperaturefor 30 minutes. The mixture was evaporated to dryness, and the residuewas dissolved in ethyl acetate (250 mL). This solution was washed withwater and dried over anhydrous magnesium sulfate. The solvent was thenremoved in vacuo leaving a dark crystalline solid (23.4 g), which waspurified by chromatography on silica gel eluting with a gradient ofethyl acetate/petroleum ether to provide the title compound as a tancrystalline solid (13.75 g), m.p. 91–93° C.

Step C. 1-(3-Phenylacetyl-pyridin-2-ylmethyl)-1H-pyrrole-2-carbaldehyde

To a stirred solution of2-(2-formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acid methyl esterof Step B (13.65 g, 55.9 mmol) in methanol (50 mL) was added sodiumhydroxide (2.2 g, 55.9 mmol.). The reaction mixture was refluxed undernitrogen for 2 hours, and then the solvent was removed in vacuo. Aportion of the residual yellow solid.(5 g) was suspended in a mixture ofbenzyl alcohol (20 mL) and benzene (30 mL). Diphenylphosphoryl azide(6.54 g, 1.2 equiv.) was added, and the reaction was slowly heated toreflux. After refluxing for 1 hour, the mixture was cooled and washedwith water, dried over anhydrous magnesium sulfate, filtered andevaporated to dryness to provide the title compound as a tan crystallinesolid (4.4 g), m.p. 109–111° C.

Step D. 9,10-Dihydro-4H-3a,5,9-triaza-benzo[f]azulene

A stirred mixture of1-(3-phenylacetyl-pyridin-2-ylmethyl0-1H-pyrrole-2-carbaldehyde of StepC (1.0 g), in ethyl acetate (10 mL) containing 10% palladium on charcoal(10 mg.), magnesium sulfate (0.010 g) and 5 drops of acetic acid washydrogenated at atmospheric pressure until hydrogen uptake ceased. Thereaction mixture was then filtered through Celite and the solventremoved in vacuo. The crude product (yellow crystalline solid, 0.530 g)was purified by chromatography on silica gel eluting with a gradient ofethyl acetate in petroleum ether to provide the title product as ayellow crystalline solid, m.p. 171–172° C.

Step E. (4-Bromo-3-methyl-phenyl)-(4H, 10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone

To a stirred solution of the9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (1.0 g) indichloromethane (10 mL) was added 3-methyl-4-bromobenzoyl chloride (1.39g) and triethylamine (1.1 mL). After stirring for 2.5 hours, thereaction mixture was washed with water, dried over anhydrous magnesiumsulfate, filtered and the solvent removed in vacuo to provide the titleproduct as a tan crystalline solid (2.3 g), which was used withoutfurther purification.

Step F. (2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-(4H, 10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone

A stirred mixture of (4-bromo-3-methyl-phenyl)-(4H, 10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone of Step E (1.0 g),2-trifluoromethyl-boronic acid (1.49 g, 3.0 equiv.), potassium phosphate(2.2 g) and a catalytic amount (0.050 g) of tetrakis(triphenylphosphine)palladium (0) in dioxane (10 mL) was refluxed for 2 hours. The solventwas then removed in vacuo and the residue dissolved in dichloromethane.The solution was then washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated to dryness. The residue was thenchromatographed on silica gel eluting with 5% ethyl acetate indichloromethane to yield a colorless gum which crystallized uponaddition of a little diethyl ether to provide the title compound as acream-colored crystalline solid (0.500 g), m.p. 153–155° C.

¹H NMR (DMSO-d₆, 400 MHz): δ 1.85 (s, 3H), 5.10 (s, 2H), 5.40 (s, 2H),5.90 (t, 1H), 6.00 (s, 1H), 6.90 (t, 1H), 6.94 (d, 1H), 7.03 (d, 1H),7.12 (dd, 1H), 7.23 (d, 1H), 7.28 (s, 1H), 7.37 (d, 1H), 7.58 (t, 1H),7.68 (t, 1H), 7.80 (d, 1H), 8.27 (d, 1H)

MS [(+)ESI, m/z]: 448 [M+H]⁺.

Anal. Calcd. for C₂₆H₂₀F₃N₃O: C, 69.79, H, 4.51, N, 9.39. Found: C,69.91, H, 4.30, N, 9.26).

Step G.2,2,2-Trichloro-1-{[9-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulen-3-yl}-ethanone

To a solution of (2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-(4H,10H-3a, 5,9-triaza-benzo[f]azulen-9-yl)-methanone in methylene chloridewas added trichloroacetyl chloride (1.1 equiv.) and triethylamine (1.5equiv,) After stirring overnight at room temperature, the reaction waswashed with water, dried over anhydrous magnesium sulfate, andevaporated to dryness to provide the crude title compound which was usedas such in the next step.

Step H.9-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4yl)carbonyl]-9,10-dihydro-3a,5,9-triaza-benzo[f]azulen-3-carboxylicacid

To a solution of2,2,2-trichloro-1-{[9-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulen-3-yl}-ethanoneof Step G in acetone was added 2.5 N sodium hydroxide (1.0 equiv.).After stirring overnight, the solvent was removed in vacuo leaving thecrude sodium salt of the carboxylic acid. This was dissolved inanhydrous ethanol and treated with 2 N hydrochloric acid (1.0 equiv.).The solvent was removed in vacuo, the residue redissolved in anhydrousethanol and the solvent again removed in vacuo. The crude title compoundwas then dried in vacuo over phosphorus pentoxide.

Step I.{[[3-(Pyridin-2-ylmethyl)amino]carbonyl]-4H-10H-3a,5,9-triaza-benzo[f]azulen-9-yl}-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone

To a solution of the9-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4yl)carbonyl]-9,10-dihydro-3a,5,9-triaza-benzo[f]azulen-3-carboxylicacid (3.38 mmol) of Step H in N,N-dimethylformamide (20 mL) was added1-hydroxybenzotriazole (1.1 equiv.) and[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.2equiv.), followed by 2-(aminomethyl)pyridine (1.2 equiv.) andN,N-diisopropylethyl amine (1.5 equiv.). The reaction mixture wasstirred overnight, then diluted with ethyl acetate and washed with waterand saturated aqueous sodium bicarbonate. The organic phase was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo.Purification of the residue was effected by chromatography on silica geleluting with a gradient of methanol in ethyl acetate to provide thetitle compound as a white foam.

The compounds of following Examples 24–143 were prepared according tothe General Procedures A–K described below.

General Procedure A

Step A. An appropriately substituted haloaryl carboxylic acid (1.1 mol)was converted to the acid chloride by using oxalyl chloride (1.5 mmol)and a catalytic amount of N,N-dimethylformamide in dichloromethane. Uponconsumption of the acid as determined by HPLC analysis, all volatileswere removed in vacuo. The resulting residue was dissolved indichloromethane and added dropwise to a stirred and cooled (0° C.)solution of an appropriately substituted5H-pyrrolo[2,1-c][1,4]benzodiazepine (1 mmol) and N,N-diisopropylethylamine (1.2 mmol) in dichloromethane. After 1–16 hours, the mixture wasdiluted with dichloromethane and washed with 10% aqueous sodiumbicarbonate. The combined organic extracts were dried over anhydroussodium sulfate, filtered and concentrated.

Step B. To the residue was added an appropriately substituted boronicacid (1.2 mmol), potassium carbonate (2.5 mmol), tetrabutylammoniumbromide (1 mmol), palladium(II) acetate (3% mole) and water/acetonitrile(1:1, 2 mL). The contents were heated to 70° C. for 1.5 hours, thenethyl acetate was added and the organic phase washed with water. Thesolution was filtered through a small plug of Celite and concentrated todryness.

Step C. The residue was dissolved in dichloromethane andN,N-diisopropylethyl amine (2 mmol) was added. The flask was purged withnitrogen and trichloroacetyl chloride was added dropwise to the stirredreaction mixture. After 16 hours, the reaction was quenched by addingaqueous potassium carbonate (100 g/300 mL) and the organic phaseremoved. The aqueous layer was extracted with additional dichloromethaneand the combined extracts dried over anhydrous sodium sulfate, filteredand concentrated.

Step D. The crude product from Step C was dissolved in tetrahydrofuran(1 mL) and 2N sodium hydroxide (1.5 mL) was added. The mixture washeated (70° C.) for 1.5 hours, 2N hydrochloric acid was added and theproduct extracted with ethyl acetate. The organic phase was dried,filtered and concentrated. The residue was purified by columnchromatography using a gradient of ethyl acetate in hexane contaning 1%glacial acetic acid as the eluant.

Step E. To a stirred solution of a carboxylic acid of Step D above (1.85mmol) in anhydrous tetrahydrofuran (14 mL) was added 1,1′-carbonyldiimidazole in one portion. The mixture was stirred at room temperature(6–8 hours). The progress of the reaction was monitored by HPLC and whenthe starting carboxylic acid was consumed, the mixture was worked up toprovide the intermediate imidazolide.

Step F. An aliquot of a tetrahydrofuran solution (400 μL, 0.05 mmole)containing the imidazolide of Step E (0.05 mmol) was treated with a 0.25M solution of an appropriate amine (0.1 mmol). The mixture was heated at60° C. and the progress of the reaction followed by HPLC. The solventwas removed and the residue dissolved in dichloromethane (1 mL). Theorganic phase was washed with brine-water (1:1, v/v, 1 mL) and theaqueous layer extracted with additional dichloromethane. The combinedextracts were dried and evaporated to dryness and the residue purifiedby flash chromatography on silica gel. The column (prepacked in 2.5%methanol in dichloromethane contaning 1% triethylamine) was eluted witha solvent gradient from 2.5 to 5% methanol in dichloromethane, toprovide the desired title compound. The desired title compounds wereeither obtained as crystalline solids by exposure to diethyl ether orwere further converted into their salts by any of the followingprocedures.

Step G. Compounds prepared according to Step E that dissolved in diethylether were treated with a stoichiometric amount of 1N hydrochloric acidin diethyl ether whereby the hydrochloride salts precipitated out aswhite solids. Compounds that did not conform to the above category, weredissolved in the minimal amount of tetrahydrofuran, then diluted withdiethyl ether. The hydrochloride salts were formed upon addition of 1Nhydrochloric acid in diethyl ether with stirring. Compounds that did notimmediately precipitate out of solution were stirred for 12–16 hourswhereupon a white solid precipitated out.

General Procedure B

To a stirred solution of an appropriately substituted carboxylic acid ofGeneral Procedure A, Step D (2 mmol), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (0.229 g, 2.2 mmol) and a catalytic amount of4-(dimethylamino)pyridine in dichloromethane (6 mL) was added theappropriately substituted amine (2.2 mmol) in dichloromethane (2 mL).The reaction was allowed to stir at room temperature for 16 hours, thendiluted with dichloromethane. The organic layer was washed with water,saturated aqueous sodium bicarbonate, dried over anhydrous sodiumsulfate and evaporated to dryness. The residue was purified by flashchromatography on silica gel (prepacked in dichloromethane containing2.5% methanol and 1% triethylamine and eluted with a solvent gradient of2.5 to 5% methanol in dichloromethane) to provide the desired titlecompound.

General Procedure C

Triphosgene (742 mg, 2.5 mmol) was added to a stirred solution of acarboxylic acid of General Procedure A, Step D (5.0 mmol) indichloromethane (10 mL). The clear solution was allowed to stir at roomtemperature (14 hours) after which time the solution turned red. To thereaction mixture was added a solution of the required amine (10.0 mmol)and N,N-diisopropylethyl amine (10.0 mmol) in dichloromethane (5 mL).The mixture was diluted with dichloromethane and washed with water andbrine. The organic phase was dried, filtered and concentrated to afforda residue which was purified by flash chromatography on silica gel. Thecolumn (prepacked in 2.5% methanol in dichloromethane contaning 1%triethylamine) was eluted with a solvent gradient from 2.5 to 5%methanol in dichloromethane, to provide the title compound.

General Procedure D

A stirred solution of a carboxylic acid of General Procedure A, Step D(3.54 mmol) and the appropriately substituted amine (3.72 mmol) inN,N-dimethylformamide (10 mL) was cooled to 0° C. N,N-diisopropylethylamine (3.89 mmol) was added and the mixture stirred for five minutes.O-(1-Benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU) (1.42 g, 3.72 mmol) was added to the mixture in one portion. HPLCanalysis revealed that the reaction was complete within five minutes.The solvent was removed at reduced pressure. The residue was dilutedwith water and extracted with ethyl acetate. The combined extracts weredried and concentrated to dryness. The residue was purified by flashchromatography on silica gel (prepacked in ethyl acetate containing 2%triethylamine and eluted with 100% ethyl acetate) to provide the titlecompound.

General Procedure E

To a 0.25 M solution of a carboxylic acid of General Procedure A, Step D(200 μL) in N,N-dimethylformamide was added sequentially a 0.5 Msolution of N,N-diisopropylethyl amine (200 μL) in N,N-dimethylformamideand a 0.25 M solution ofO-(7-aza-1-benzotriazolyl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (210 μL) in N,N-dimethylformamide. Themixture was stirred vigorously at room temperature and then a 0.25 Msolution of the appropriately substituted amine (200 μL) inN,N-dimethylformamide was added. Stirring was continued for 24 hours atroom temperature, then the mixture was diluted with ethyl acetate, andwashed with 1:1 water/brine. The organic layer was dried andconcentrated to dryness. The residue was purified by flashchromatography on silica gel (prepacked in ethyl acetate containing 2%triethylamine and eluted with 100% ethyl acetate) to provide the titlecompound.

General Procedure F

Step A. To a solution of an appropriately substituted anilino carboxylicacid in methanol was added thionyl chloride. The mixture was heated for16 hours. The volatiles were removed under reduced pressure and thehydrochloride salt of the carboxylic acid methyl ester was recoveredafter trituration with methanol/diethyl ether. The solid was dissolvedin concentrated hydrochloric acid and cooled. An aqueous solution ofsodium nitrite was added and the mixture was stirred at 0° C. for onehour. An aqueous solution of KI/I₂ was prepared and added to the cooledmixture so that the reaction temperature did not exceed 0° C. After 1–2hours the reaction was complete as evidenced by TLC/HPLC analysis. Theproduct was recovered by extraction with ethyl acetate. The combinedextracts were dried, filtered and concentrated to afford the desiredsubstituted aryl iodide which could be further purified byrecrystallization.

Step B. To a solution of an appropriately substituted aryl halide methylester of Step A (2 mmol) and an appropriately substituted boronic acid(2 mmol) in 20% aqueous acetone was added cesium carbonate (3 mmol)followed by palladium(II) acetate (60 μmol). The mixture was heated (70°C.) with stirring for 8–16 hours. The reaction was concentrated toremove the acetone after TLC/HPLC analysis indicated the reaction wascomplete. The aqueous phase was extracted with ethyl acetate and thecombined extracts were filtered through a pad of Celite. The filtratewas washed with 5% aqueous sodium bicarbonate and brine, dried overanhydrous sodium sulfate, filtered and evaporated to dryness. Theresidue was purified by flash chromatography on silica gel.

Step C. The product from Step B was dissolved in tetrahydrofuran (1 mL)and 2N sodium hydroxide (1.5 mL) was added. The mixture was heated (70°C.) for 1.5 hours, 2N hydrochloric acid was added and the productextracted with ethyl acetate. The organic phase was dried, filtered andconcentrated. The residue was purified by column chromatography usingethyl acetate in hexane contaning 1% glacial acetic acid as the eluant.

Step D. To a suspension of the carboxylic acid of Step C (60 μmol) indichloromethane (100 μL) was added a 0.45 M solution of oxalyl chloride(200 μL) in dichloromethane followed by dichloromethane (100 μL)containing a catalytic amount of N,N-dimethylformamide. The mixture wasallowed to sit at room temperature for 16 hours, then the volatiles wereremoved in vacuo to afford the crude acid chloride. A solution of theacid chloride in tetrahydrofuran (0.3 M, 200 μL), was utilized toacylate a solution (0.3 M, 200 μL) of an appropriately substituted5H-pyrrolo[2,1-c][1,4]benzodiazepine in tetrahydrofuran according to theGeneral Procedure A, Step A.

General Procedure G

A mixture of an appropriately substituted aryl bromide methyl ester (oran aryl iodide methyl ester of General Procedure F, Step A) (8.3 mmol),an appropriately substituted boronic acid (9.1 mmol), potassiumcarbonate (20.8 mmol), tetrabutylammonium bromide (or iodide) (8.3mmol), palladium(II) acetate and water (8–9 mL) was stirred with heating(70° C.) for 1.5 hours, whereupon the reaction was deemed complete byHPLC analysis. The oily upper layer was extracted with ethyl acetate,the extracts washed with brine, dried and concentrated to dryness. Theresidue was filtered through a column of silica gel to provide thedesired coupled product of General Procedure F, Step B.

General Procedure H

The coupling of an appropriately substituted aryl bromide methyl ester(or an aryl iodide methyl ester of General Procedure F, Step A) (8.3mmol) to an appropriately substituted pyridyl borane was carried outusing potassium hydroxide as the base, in the presence oftetrabutylammonium bromide (or iodide) and a tetrakis(triphenylphoshine)palladium (0) catalyst essentially according to the published procedureof M. Ishikura, Synthesis, 936–938 (1994), to provide the desiredcoupled product of General Procedure F, Step B.

General Procedure I

The coupling of an appropriately substituted aryl bromide methyl ester(or an aryl iodide methyl ester of General Procedure F, Step A) (8.3mmol) to an appropriately substituted boronic acid was carried outessentially according to General Procedure F, Step B except that thesolvent was acetonitrile.

General Procedure J

The desired substituted aryl iodide of General Procedure F, Step A wasprepared by reaction of an appropriately substituted amino carboxylicacid in concentrated hydrochloric acid at 0° C. with an aqueous solutionof sodium nitrite followed by the addition of an aqueous solution ofKI/I₂ at 0° C., followed by esterification of the resulting iodo arylcarboxylic acid with methanolic hydrochloric acid.

General Procedure K

The acylation of an activated appropriately substituted arylpyridinecarboxylic acid of Procedure H was carried out by dissolving the acid(0.06 mmol) in a solution of oxalyl chloride in dichloromethane (12mg/200 μL) followed by a catalytic amount of N,N-dimethylformamide indichloromethane (100 μL). After stirring at room temperature for 16hours, the volatiles were removed and tetrahydrofuran added, followed bythe addition of a solution of the appropriately substituted5H-pyrrolo[2,1-c][1,4]benzodiazepine and N,N-diisopropylethyl amine (1:2molar ratio) in tetrahydrofuran. After stirring for 20 hours, thereaction was worked up essentially as described in General Procedure A,Step A.

EXAMPLE 2410-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23874. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 2510-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23831. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 2610-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 529.22343. Calcd. for C₃₃H₂₉N₄O₃: 529.22342

EXAMPLE 2710-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 513.22772. Calcd. for C₃₃H₂₉N₄O₂: 513.22851

EXAMPLE 2810-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23855. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 2910-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 577.20052. Calcd. for C₃₄H₃₀ClN₄O₃: 577.20010

EXAMPLE 3010-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 593.19557. Calcd. for C₃₄H₃₀ClN₄O₄: 593.19501

EXAMPLE 3110-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 579.23816. Calcd. for C₃₇H₃₁N₄O₃: 579.23907

EXAMPLE 3210-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 559.23363. Calcd. for C₃₄H₃₁N₄O₄: 559.23399

EXAMPLE 3310-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 559.23423. Calcd. for C₃₄H₃₁N₄O₄: 559.23399

EXAMPLE 3410-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 583.18978. Calcd. for C₃₆H₂₈ClN₄O₂: 583.18953

EXAMPLE 3510-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 581.21516. Calcd. for C₃₄H₂₈F₃N₄O₂: 581.21589

EXAMPLE 3610-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23845. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 3710-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 527.24341. Calcd. for C₃₄H₃₁N₄O₂: 527.24416

EXAMPLE 3810-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23838. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 3910-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 529.22338. Calcd. for C₃₃H₂₉N₄O₃: 529.22342

EXAMPLE 4010-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 513.22773. Calcd. for C₃₃H₂₉N₄O₂: 513.22851

EXAMPLE 4110-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23838. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 4210-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 577.20054. Calcd. for C₃₄H₃₀ClN₄O₃: 577.20010

EXAMPLE 4310-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 593.19500. Calcd. for C₃₄H₃₀ClN₄O₄: 593.19501

EXAMPLE 4410-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 579.24077. Calcd. for C₃₇H₃₁N₄O₃: 579.23907

EXAMPLE 4510-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 559.23341. Calcd. for C₃₄H₃₁N₄O₄: 559.23399

EXAMPLE 4610-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 559.23373. Calcd. for C₃₄H₃₁N₄O₄: 559.23399

EXAMPLE 4710-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 583.18952. Calcd. for C₃₆H₂₈ClN₄O₂: 583.18953

EXAMPLE 4810-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 581.21409. Calcd. for C₃₄H₂₈F₃N₄O₂: 581.21589

EXAMPLE 4910-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 557.25366. Calcd. for C₃₅H₃₃N₄O₃: 557.25472

EXAMPLE 5010-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 541.25935. Calcd. for C₃₅H₃₃N₄O₂: 541.25981

EXAMPLE 5110-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 557.25363. Calcd. for C₃₅H₃₃N₄O₃: 557.25472

EXAMPLE 5210-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23801. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 5310-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 527.24446. Calcd. for C₃₄H₃₁N₄O₂: 527.24416

EXAMPLE 5410-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 557.25403. Calcd. for C₃₅H₃₃N₄O₃: 557.25472

EXAMPLE 5510-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 591.21606. Calcd. for C₃₅H₃₂ClN₄O₃: 591.21575

EXAMPLE 5610-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 607.21044. Calcd. for C₃₅H₃₂ClN₄O₄: 607.21066

EXAMPLE 5710-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 593.25470. Calcd. for C₃₈H₃₃N₄O₃: 593.25472

EXAMPLE 5810-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 573.24957. Calcd. for C₃₅H₃₃N₄O₄: 573.24964

EXAMPLE 5910-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 573.24949. Calcd. for C₃₅H₃₃N₄O₄: 573.24964

EXAMPLE 6010-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 597.20525. Calcd. for C₃₇H₃₀ClN₄O₂: 597.20518

EXAMPLE 6110-{[2-Methyl-2′-trifluoromethyl=[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 595.22982. Calcd. for C₃₅H₃₀F₃N₄O₂: 595.23154

EXAMPLE 6210-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 571.27074. Calcd. for C₃₆H₃₅N₄O₃: 571.27037

EXAMPLE 6310-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 605.23088. Calcd. for C₃₆H₃₄ClN₄O₃: 605.23140

EXAMPLE 6410-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 587.26595. Calcd. for C₃₆H₃₅N₄O₄: 587.26529

EXAMPLE 6510-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 571.27090. Calcd. for C₃₆H₃₅N₄O₃: 571.27037

EXAMPLE 6610-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 555.27479. Calcd. for C₃₆H₃₅N₄O₂: 555.27546

EXAMPLE 6710-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 557.25425. Calcd. for C₃₅H₃₃N₄O₃: 557.25472

EXAMPLE 68N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 541.25992. Calcd. for C₃₅H₃₃N₄O₂: 541.25981

EXAMPLE 6910-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 571.27107. Calcd. for C₃₆H₃₅N₄O₃: 571.27037

EXAMPLE 7010-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 621.22598. Calcd. for C₃₆H₃₄ClN₄O₄: 621.22631

EXAMPLE 7110-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 607.27097. Calcd. for C₃₉H₃₅N₄O₃: 607.27037

EXAMPLE 7210-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 587.26443. Calcd. for C₃₆H₃₅N₄O₄: 587.26529

EXAMPLE 7310-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 611.22029. Calcd. for C₃₈H₃₂ClN₄O₂: 611.22083

EXAMPLE 74N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 609.24719. Calcd. for C₃₆H₃₂F₃N₄O₂: 609.24719

EXAMPLE 75{10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 598.28159. Calcd. for C₃₇H₃₆N₅O₃: 598.28127

EXAMPLE 76{10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 582.28589. Calcd. for C₃₇H₃₆N₅O₂: 582.28636

EXAMPLE 77{10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 598.28309. Calcd. for C₃₇H₃₆N₅O₃: 598.28127

EXAMPLE 78{10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 584.26487. Calcd. for C₃₆H₃₄N₅O₃: 584.26562

EXAMPLE 79{10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 568.27112. Calcd. for C₃₆H₃₄N₅O₂: 568.27071

EXAMPLE 80{10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 598.28310. Calcd. for C₃₇H₃₆N₅O₃: 598.28127

EXAMPLE 81{10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 632.24224. Calcd. for C₃₇H₃₅ClN₅O₃: 632.24230

EXAMPLE 82{10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 648.23671. Calcd. for C₃₇H₃₅ClN₅O₄: 648.23721

EXAMPLE 83{10-[(3-Methoxy-4-(naphthalen-1-yl)-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+) ESI, m/z]: 634.28252. Calcd. for C₄₀H₃₆N₅O₃: 634.28127

EXAMPLE 84{10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 614.27683. Calcd. for C₃₇H₃₆N₅O₄: 614.27619

EXAMPLE 85{10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 614.27583. Calcd. for C₃₇H₃₆N₅O₄: 614.27619

EXAMPLE 86{10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 638.23142. Calcd. for C₃₉H₃₃ClN₅O₂: 638.23173

EXAMPLE 87(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[4-(2-pyridinyl)-1-piperazinyl]methanone

HRMS [(+) ESI, m/z]: 636.25827. Calcd. for C₃₇H₃₃F₃N₅O₂: 636.25809

EXAMPLE 8810-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23946. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 8910-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 527.24367. Calcd. for C₃₄H₃₁N₄O₂: 527.24416

EXAMPLE 9010-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23964. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 9110-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 529.22290. Calcd. for C₃₃H₂₉N₄O₃: 529.22342

EXAMPLE 9210-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 513.22881. Calcd. for C₃₃H₂₉N₄O₂: 513.22851

EXAMPLE 9310-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23950. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 9410-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 577.20008. Calcd. for C₃₄H₃₀ClN₄O₃: 577.20010

EXAMPLE 9510-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 593.19387. Calcd. for C₃₄H₃₀ClN₄O₄: 593.19501

EXAMPLE 9610-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 579.23927. Calcd. for C₃₇H₃₁N₄O₃: 579.23907

EXAMPLE 9710-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 559.23401. Calcd. for C₃₄H₃₁N₄O₄: 559.23399

EXAMPLE 9810-[(2,3′-Dimethoxy-[1,1′-biphenyl]4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 559.23341. Calcd. for C₃₄H₃₁N₄O₄: 559.23399

EXAMPLE 9910-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 583.18912. Calcd. for C₃₆H₂₈ClN₄O₂: 583.18953

EXAMPLE 10010-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 581.21569. Calcd. for C₃₄H₂₈F₃N₄O₂: 581.21589

EXAMPLE 10110-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 557.25414. Calcd. for C₃₅H₃₃N₄O₃: 557.25472

EXAMPLE 10210-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]4-yl)carbonyl]-N-methyl-N-(3-pyridinyImethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 557.25453. Calcd. for C₃₅H₃₃N₄O₃: 557.25472

EXAMPLE 10310-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 573.24906. Calcd. for C₃₅H₃₃N₄O₄: 573.24964

EXAMPLE 10410-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 543.23907. Calcd. for C₃₄H₃₁N₄O₃: 543.23907

EXAMPLE 105N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 527.24394. Calcd. for C₃₄H₃₁N₄O₂: 527.24416

EXAMPLE 10610-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 557.25454. Calcd. for C₃₅H₃₃N₄O₃: 557.25472

EXAMPLE 10710-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 591.21599. Calcd. for C₃₅H₃₂N₄O₃: 591.21575

EXAMPLE 10810-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 607.21037. Calcd. for C₃₅H₃₂ClN₄O₄: 607.21066

EXAMPLE 10910-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 593.25393. Calcd. for C₃₈H₃₃N₄O₃: 593.25472

EXAMPLE 11010-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 573.24936. Calcd. for C₃₅H₃₃N₄O₄: 573.24964

EXAMPLE 11110-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 597.20513. Calcd. for C₃₇H₃₀ClN₄O₂: 597.20518

EXAMPLE 112N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 595.23096. Calcd. for C₃₅H₃₀F₃N₄O₂: 595.23154

EXAMPLE 113{10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 598.28145. Calcd. for C₃₇H₃₆N₅O₃: 598.28127

EXAMPLE 114{10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 582.28638. Calcd. for C₃₇H₃₆N₅O₂: 582.28636

EXAMPLE 115{10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 598.28161Calcd. for C₃₇H₃₆N₅O₃: 598.28127

EXAMPLE 116{10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+) ESI, m/z]: 584.26455. Calcd. for C₃₆H₃₄N₅O₃: 584.26562

EXAMPLE 117{10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 568.27184. Calcd. for C₃₆H₃₄N₅O₂: 568.27071

EXAMPLE 118{10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo]2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 598.28188. Calcd. for C₃₇H₃₆N₅O₃: 598.28127

EXAMPLE 119{10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 632.24169. Calcd. for C₃₇H₃₅ClN₅O₃: 632.24230

EXAMPLE 120{10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 648.23779. Calcd. for C₃₇H₃₅ClN₅O₄: 648.23721

EXAMPLE 121{10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 634.28198. Calcd. for C₄₀H₃₆N₅O₃: 634.28127

EXAMPLE 122{10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+) ESI, m/z]: 614.27656. Calcd. for C₃₇H₃₆N₅O₄: 614.27619

EXAMPLE 123{10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]:. 614.27612. Calcd. for C₃₇H₃₆N₅O₄: 614.27619

EXAMPLE 124{10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 638.23111. Calcd. for C₃₉H₃₃ClN₅O₂: 638.23173

EXAMPLE 12510-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 587.26570. Calcd. for C₃₆H₃₅N₄O₄: 587.26529

EXAMPLE 12610-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]:. 571.27020. Calcd. for C₃₆H₃₅N₄O₃: 571.27037

EXAMPLE 12710-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 555.27738. Calcd. for C₃₆H₃₅N₄O₂: 555.27546

EXAMPLE 12810-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 571.27053. Calcd. for C₃₆H₃₅N₄O₃: 571.27037

EXAMPLE 12910-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 557.25454. Calcd. for C₃₅H₃₃N₄O₃: 557.25472

EXAMPLE 130N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 541.25983. Calcd. for C₃₅H₃₃N₄O₂: 541.25981

EXAMPLE 13110-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 571.27053. Calcd. for C₃₆H₃₅N₄O₃: 571.27037

EXAMPLE 13210-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 605.23199. Calcd. for C₃₆H₃₄ClN₄O₃: 605.23140

EXAMPLE 13310-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 621.22570. Calcd. for C₃₆H₃₄ClN₄O₄: 621.22631

EXAMPLE 13410-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 607.27001. Calcd. for C₃₉H₃₄N₄O₃: 607.27037

EXAMPLE 13510-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 587.26451. Calcd. for C₃₆H₃₅N₄O₄: 587.26529

EXAMPLE 13610-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 611.22112. Calcd. for C₃₈H₃₂ClN₄O₂: 611.22083

EXAMPLE 137N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 609.24693. Calcd. for C₃₆H₃₂F₃N₄O₂: 609.24719

EXAMPLE 138{10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone

HRMS [(+)ESI, m/z]: 597.28526. Calcd. for C₃₈H₃₇N₄O₃: 597.28602

EXAMPLE 139{10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone

HRMS [(+)ESI, m/z]: 583.26953. Calcd. for C₃₇H₃₅N₄O₃: 583.27037

EXAMPLE 140{10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone

HRMS [(+)ESI, m/z]: 631.24693. Calcd. for C₃₈H₃₆ClN₄O₃: 631.24705

EXAMPLE 141{10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone

HRMS [(+)ESI, m/z]: 613.28118. Calcd. for C₃₈H₃₇N₄O₄: 613.28094

EXAMPLE 142(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[2-(3-pyridinyl)-1-piperidinyl]methanone

HRMS [(+)ESI, m/z]: 635.26206. Calcd. for C₃₈H₃₄F₃N₄O₂: 635.26284

EXAMPLE 143[3-Methoxy4-(pyridin-3-yl)-phenyl]-{3-[4-(pyridin-4-yl)-piperazin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone

MS [(+)ESI, m/z]: 585 [M+H]⁺. Calcd. for C₃₅H₃₃N₆O₃: 585.261

The compounds of following Examples 144–147 were prepared according tothe general procedures described below.

General Procedure L

Step A. To a stirred cooled (0° C.) solution of an appropriatelysubstituted10-(4-amino)benzoyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine(10 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethylamine (2.09 mL, 12 mmol) followed by the addition of 9-fluorenylmethylchloroformate (2.85 g, 11 mmol) in one portion. The reaction was allowedto warm to room temperature. TLC analysis was used to monitor theprogress of the reaction and after 8 hours, indicated that a singleproduct was formed. The reaction mixture was diluted withdichloromethane and washed with water and brine. The organic phase wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by flash column chromatography (BiotageFlash 40S, gradient elution from 10 to 20% ethyl acetate in hexanes) toprovide the desired appropriately substituted4-(fluorenylmethoxycarbonyl)-10,1-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

Step B. Trichloroacetyl chloride (3.35 mL, 30 mmol) was added to asolution of an appropriately substituted4-(fluorenylmethoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step A (10 mmol) and N,N-diisopropylethyl amine (3.48 mL, 20 mmol) indichloromethane, and the solution was stirred at ambient temperature for2 hours. An aqueous solution of sodium bicarbonate (0.5 M) was added tothe mixture and the organic layer was separated, dried over anhydroussodium sulfate, filtered and concentrated. The residue was dissolved ina solution of piperidine in N,N-dimethyl formamide (20%, v/v) andstirred until the starting material was no longer observed by HPLC/TLCanalysis. The mixture was diluted with ethyl acetate and washed withwater. The organic phase was dried over anhydrous sodium sulfate,filtered and concentrated. The desired appropriately substituted2,2,2-trichloro-1-[10-(4-aminobenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}-ethanonewas isolated by flash chromatography (Biotage, Flash 40M, gradientelution from 20 to 30% ethyl acetate in hexanes).

Step C. An appropriately substituted 1,4-diketone (25 mmol) was added toa vial containing an appropriately substituted aniline of Step B (4.4mmol) followed by the addition of acetic acid (1 mL). The contents ofthe vial were stirred and heated (80° C.) without the vial capped (toallow for the removal of water). After 1 hour the solution was dilutedwith ethyl acetate (20 mL). The organic phase was washed with water,aqueous sodium bicarbonate and brine. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated. The resultingresidue was purified by flash column chromatography to afford thedesired appropriately substituted2,2,2-trichloro-1-{10-{4-(1H-pyrrol-1-yl)-benzoyl]-10,11-dihydro[2,1-c][1,4]benzodiazepin-3-yl}-ethanone.

Step D. The material from Step C (3.85 mmol) was dissolved intetrahydrofuran (10 mL) and treated with aqueous sodium hydroxide (2 N,3 mL). The mixture was allowed to stir with heating (80° C.) overnight.After cooling to room temperature, aqueous hydrochloric acid (2 N, 3.2mL) was added and product was recovered by extraction with ethylacetate. The combined extracts were evaporated and the residue purifiedby flash column chromatography, eluting with a gradient of 20 to 50%ethyl acetate in hexanes to provide the desired appropriatelysubstituted title compound.

EXAMPLE 14410-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-N-[2-(pyridin-2-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 574.28119. Calcd. for C₃₅H₃₆N₅O₃: 574.28127

EXAMPLE 145{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-2-yl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 601.29180. Calcd. for C₃₆H₃₇N₆O₃: 601.29217

EXAMPLE 146{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-4-yl)-1-piperazinyl]methanone

HRMS [(+)ESI, m/z]: 601.29177. Calcd. for C₃₆H₃₇N₆O₃: 601.29217

EXAMPLE 14710-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-N-[2-(pyridin-4-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

HRMS [(+)ESI, m/z]: 574.28047. Calcd. for C₃₅H₃₆N₅O₃: 574.28127

1. A compound of the formula:

wherein:

R₁ and R₂ are, independently, selected from hydrogen, (C₁–C₆)loweralkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁–C₆) loweralkylamino, (C₁–C₆) lower alkoxy, —OCF₃, (C₁–C₆) lower alkoxy carbonyl,—NHCO[(C₁–C₆)lower alkyl], carboxy, —CONH₂, —CONH[(C₁–C₆) lower alkyl],or —CON[(C₁–C₆) lower alkyl]₂; R₃ is a substituent selected fromhydrogen, (C₁–C₆) lower alkyl, (C₁–C₆) lower alkoxy, hydroxy, amino,(C₁–C₆) lower alkylamino, CO lower alkyl (C₁–C₆), or halogen; R₄ is themoiety B–C; wherein: B is selected from the group of:

and C is selected from the group of:

wherein: A is CH or N; R₅, R₆, R₇, R₈, R₉, R₁₀ are, independently,selected from hydrogen, (C₁–C₆) lower alkyl, (C₁–C₆) lower alkoxy,(C₁–C₆) lower alkylcarbonyl, (C₃–C₆) lower alkenyl, (C₃–C₆) loweralkynyl, (C₃–C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy,alkoxycarbonyl, cycloalkyloxycarbonyl, aryl alkyloxycarbonyl, carbamoyl,—O—CH₂—CH═CH₂, halogen, halo lower alkyl, trifluoromethyl, OCF₃, S(loweralkyl), —OC(O)N[lower alkyl]₂, —CONH[lower alkyl], —CON[lower alkyl]₂,lower alkylamino, di-lower alkylamino, lower alkyl di-lower alkylamino,hydroxy, cyano, trifluoromethylthio, nitro, amino, lower alkylsulfonyl,aminosulfonyl, lower alkylaminosulfonyl,

phenyl or naphthyl; R₁₁ and R₁₂ are, independently, selected from thegroup of hydrogen, (C₁–C₆) lower alkyl, (C₂–C₆) lower alkenyl, (C₃–C₆)lower alkynyl, hydroxy (C₁–C₆) lower alkyl, alkoxy (C₁–C₆) lower alkyl,acyloxy (C₁–C₆) lower alkyl, cyclo lower alkyl, or aryl, optionallysubstituted by hydroxy, (C₁–C₆) lower alkoxy, halogen, cyano,SO₂[(C₁–C₆) lower alkyl], or —S[(C₁–C₆) lower alkyl]; and R is selectedfrom the groups:

wherein: R₁₃ is selected from hydrogen, (C₁–C₆) lower alkyl, cyanoethylor

R₁₄ is selected from hydrogen or (C₁–C₆) lower alkyl; R₁₅ is one or twosubstituents selected from the group of hydrogen, (C₁–C₆) lower alkyl,halogen, trifluoromethyl, (C₁–C₆) lower alkoxy, (C₁–C₆) loweralkoxycarbonyl, or

R₁₆ represents one to two substituents selected from hydrogen, or(C₁–C₆) lower alkyl; m is an integer from 0 to 2; n is an integer from 1to 2; and p is an integer from 0 to 1; or a pharmaceutically acceptablesalt form thereof.
 2. A compound having the formula:

wherein:

R₁ and R₂ are independently selected from H, (C₁–C₆)lower alkyl,halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁–C₆) loweralkylamino, (C₁–C₆) lower alkoxy, —OCF₃, (C₁–C₆) lower alkoxycarbonyl,—NHCO[(C₁–C₆)lower alkyl], carboxy, —CONH₂, —CONH (C₁–C₆) lower alkyl,or —CON[(C₁–C₆) lower alkyl]₂; R₃ is a substituent selected fromhydrogen, (C₁–C₆) lower alkyl, (C₁–C₆) lower alkoxy, hydroxy, amino,(C₁–C₆) lower alkylamino, —CO lower alkyl (C₁–C₆), or halogen; R₄ is themoiety B–C; wherein: B is selected from the group of:

and C is selected from the group of:

A is CH or N; R₅, R₆, R₇, R₈, R₉ and R₁₀ are independently selected fromH, (C₁–C₆) lower alkyl, (C₁–C₆) lower alkoxy, hydroxy (C₁–C₆) loweralkyl, alkoxy (C₁–C₆) lower alkyl, acyloxy (C₁–C₆) lower alkyl, (C₁–C₆)lower alkylcarbonyl, (C₃–C₆) lower alkenyl, (C₃–C₆) lower alkynyl,(C₃–C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, alkoxycarbonyl,cycloalkyloxycarbonyl, carbamoyl, —O—CH₂—CH═CH₂, halogen, halo loweralkyl, trifluoromethyl, —OCF₃, —S(lower alkyl), —OC(O)N[lower alkyl]₂,—CONH(lower alkyl), —CON[lower alkyl]₂, lower alkylamino, di-loweralkylamino, lower alkyl di-lower alkylamino, hydroxy, cyano,trifluoromethylthio, nitro, amino, lower alkylsulfonyl, aminosulfonyl,or lower alkylaminosulfonyl; R₁₁ and R₁₂ are, independently, selectedfrom the group of hydrogen, (C₁–C₆) lower alkyl, (C₂–C₆) lower alkenyl,(C₃–C₆) lower alkynyl, hydroxy (C₁–C₆) lower alkyl, alkoxy (C₁–C₆) loweralkyl, acyloxy (C₁–C₆) lower alkyl, cyclo lower alkyl, or aryl,optionally substituted by hydroxy, (C₁–C₆) lower alkoxy, halogen, orcyano; R is selected from any of the following groups:

wherein: R₁₃ is selected from H, (C₁–C₆) lower alkyl, or cyanoethyl; R₁₄is selected from H or (C₁–C₆) lower alkyl; R₁₅ is one or twosubstituents selected independently from hydrogen, (C₁–C₆) lower alkyl,halogen, trifluoromethyl, (C₁–C₆) lower alkoxy, (C₁–C₆) loweralkoxycarbonyl; R₁₆ and R_(16′) are selected independently fromhydrogen, or (C₁–C₆) lower alkyl; m is an integer from 0 to 2; n is aninteger from 1 to 2; and p is an integer from 0 to 1; or apharmaceutically acceptable salt form thereof.
 3. A compound of claim 1selected from the group of: a)[10-(2-Methyl-2′-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-(4-pyridin-4-yl-piperazin-1-yl)-methanone;b)10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-3-({4-[(1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine;c)3-({4-[(2-Methyl-1-oxidopyridin-3-yl)methyl]piperazin-1-yl}carbonyl)-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine;d)N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[(1-oxidopyridin-3-yl)methyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(2′,6-Dichloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-(1-oxo-pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[4-(Naphthalen-1-yl)-benzoyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 4. A compound ofclaim 1 selected from the group of: a){[10-(4-Methyl-napthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-4-yl)-1-piperazinyl]methanone;b)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-methyl-N-[2-(pyridin-4-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)N-Methyl-10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)-carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide;d)7,8-Dimethoxy-{10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-yl}[4-(pyridin-2-yl)-1-piperazinyl]methanone;e)10-[(6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(pyridin-2-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-yl)carbonyl]-N-methyl-N-[2-(pyridin-2-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxamide;h)10-[(6-Phenyl-pyridin-3-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)[3-Methyl-4-(pyridin-4-yl)-phenyl]-{3-[4-(pyridin-2-yl)-piperazin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone;or a pharmaceutically acceptable salt form thereof.
 5. A compound ofclaim 1 selected from the group of: a)10-[(3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[(2′-Chloro-2-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(pyridin-2-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide;c){[[3-(Pyridin-2-ylmethyl)amino]carbonyl]-4H-10H-3a,5,9-triaza-benzo[f]azulen-9-yl}-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone;d)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 6. A compound ofclaim 1 selected from the group of: a)10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;d)10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(2-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 7. A compound ofclaim 1 selected from the group of: a)10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;d)10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 8. A compound ofclaim 1 selected from the group of: a)10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;d)10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;j)10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or k)10-{[2-Methyl-2′-trifluoromethyl=[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 9. A compound ofclaim 1 selected from the group of: a)10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;d)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 10. A compound ofclaim 1 selected from the group of: a)10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(2-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;d){10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;e){10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;f){10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;g){10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;h){10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;i){10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;or a pharmaceutically acceptable salt form thereof.
 11. A compound ofclaim 1 selected from the group of: a){10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;b){10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;c){10-[(3-Methoxy-4-(naphthalen-1-yl)-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;d){10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;e){10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;f){10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-pyridinyl)-1-piperazinyl]methanone;g)(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[4-(2-pyridinyl)-1-piperazinyl]methanone;h)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 12. A compound ofclaim 1 selected from the group of: a)10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;d)10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-(4-pyridinylmethyl)-10,11dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(4-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 13. A compound ofclaim 1 selected from the group of: a)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;d)10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 14. A compound ofclaim 1 selected from the group of: a)10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-(3-pyridinylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c){10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;d){10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;e){10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;f){10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;g){10-[(2′-Methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;h){10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;i){10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;or j){10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;or a pharmaceutically acceptable salt form thereof.
 15. A compound ofclaim 1 selected from the group of: a){10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;b){10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;c){10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;d){10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(4-pyridinyl)-1-piperazinyl]methanone;e)10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h)10-[(3′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;i)10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or j)N-Methyl-10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 16. A compound ofclaim 1 selected from the group of: a)10-[(2-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;b)10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;c)10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;d)10-[3-Methoxy-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e)10-[(2,3′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;f)10-[2-Chloro-4-(naphthalen-1-yl)benzoyl]-N-methyl-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;g)N-Methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-[2-(4-pyridinyl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;h){10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone;i){10-[(2′-Methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone;or j){10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone;or a pharmaceutically acceptable salt form thereof.
 17. A compound ofclaim 1 selected from the group of: a){10-[(2,2′-Dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[2-(3-pyridinyl)-1-piperidinyl]methanone;b)(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)[2-(3-pyridinyl)-1-piperidinyl]methanone;c)[3-Methoxy-4-(pyridin-3-yl)-phenyl]-{3-[4-(pyridin-4-yl)-piperazin-1-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl-methanone;d)10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-N-[2-(pyridin-2-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;e){10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-2-yl)-1-piperazinyl]methanone;f){10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(pyridin-4-yl)-1-piperazinyl]methanone;or g)10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-N-methyl-N-[2-(pyridin-4-yl)ethyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 18. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt form thereof, and apharmaceutically acceptable carrier or excipient.
 19. A method forinhibiting or preventing pre-term labor, dysmenorrhea, or endometritisin a mammal, the method comprising administering to a mammal in needthereof a pharmaceutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt form thereof.
 20. A compound that is10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-8-[(piperidin-1-yl)carbonyl]-N-(pyridin-4-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamideor a pharmaceutically acceptable salt form thereof.
 21. A method forinhibiting pre-term labor, dysmenorrhea, or endometritis in a mammal,the method comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of claim 20, or apharmaceutically acceptable salt form thereof.
 22. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof claim 2, or a pharmaceutically acceptable salt form thereof, and apharmaceutically acceptable carrier or excipient.
 23. A method forinhibiting pre-term labor, dysmenorrhea, or endometritis in a mammal,the method comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of claim 2, or apharmaceutically acceptable salt form thereof.